Review Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity
Babiker M. El-Haj 1,* and Samrein B.M. Ahmed 2
1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, University of Science and Technology of Fujairah, Fufairah 00971, UAE 2 College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 00971, UAE; [email protected] * Correspondence: [email protected]
Received: 6 February 2020; Accepted: 7 April 2020; Published: 22 April 2020
Abstract: Alkyl moieties—open chain or cyclic, linear, or branched—are common in drug molecules. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some hydroxy metabolites, which are equiactive with their parent drugs, have been developed into ester prodrugs while carboxy metabolites, which are equiactive to their parent drugs, have been developed into drugs as per se. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. The review provides a basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules, and (ii) pharmacologic activity of the metabolites resulting from hydroxy and/or carboxy functionalization of alkyl moieties.
Keywords: alkyl moieties; hydroxy functionalization; carboxy functionalization; prodrug metabolic activation; primary and auxiliary pharmacophores; auxophores
1. Introduction Nonpolar alkyl moieties are frequently incorporated into drug molecules to serve pharmacodynamic and/or pharmacokinetic purposes. Being lipophilic, alkyl moieties are metabolized in phase I via hydroxy functionalization to alcohols—a process which is, in some cases, followed by carboxy functionalization. Usually, the carboxyl and sterically unhindered hydroxyl groups in the resulting metabolites are conjugated in phase II by glucuronic acid. The chemical forms and metabolic products of the alkyl moieties surveyed in this review are summarized in Table1.
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Table 1. Moieties metabolized by hydroxy and carboxy functionalization.
Aliphatic moieties metabolized by oxidative Molecules 2020, 25, 1937 Metabolic products 2 of 29 hydroxylation Primary, secondary, or tertiary alcohols, Table 1. Moieties metabolized by hydroxydepending and carboxy on functionalization. the class of substrate carbon; Alkyl (linear or branched) primary alcohols are further oxidized to Aliphatic Moieties Metabolized by Metabolic Products Oxidative Hydroxylation carboxylic acids Unhindered methylene groups in alicycles and Primary, secondary, or tertiary alcohols, depending on the aliphatic Alkylheterocycles (linear or (usually branched) at the farthest class of substrate carbon;Secondary primary alcohols alcohols are further position from the monosubstituent) oxidized to carboxylic acids Unhindered methylene groups in alicycles and Primary alcohols, followed by oxidation to Benzylic methyl groups aliphatic heterocycles (usually at the farthest Secondarycarboxyl alcohols group position from the monosubstituent) Methyl groups bonded to alicycles or Primary alcohols, followed by oxidation to Benzylicheterocycles methyl groups Primary alcohols, followedcarboxyl by oxidation groups to carboxyl group MethylMethylene groups groups bonded alpha to alicycles to both or heterocycles carbonyl and Primary alcohols, followed by oxidation to carboxyl groups Secondary alcohols Methylene groups alpha to both carbonyl and imino groups Secondary alcohols imino groups Secondary alcohol; usually followed by Secondary alcohol; usually followed by carbonyl compound CarbonsCarbons α toto a a heteroatom heteroatom in ain heterocycle a heterocycle carbonyl compound (aldehyde or ketone) (aldehyde or ketone) elimination elimination Primary alcohols in open-chain alkyls and secondary Allylic carbons Primary alcohols in open-chain alkyls and Allylic carbons alcohols in alicycles secondary alcohols in alicycles
Generally, alkylsalkyls are found in drug molecules in their capacity as functional groups or as frameworks for (or carriers of) hydrophilic or other hydrophobic functional groups. Usually, Usually, internal ω linear alkyls assume the role of frameworks,frameworks, while ω methyls of terminal linear or branched alkyls assume primary or auxiliary pharmacophoric roles by interacting with biological targets through van der Waals binding.binding. In In addition, internal internal linear linear alkyls alkyls may be used as spacers between functional groups for didifferentfferent purposes—mainlypurposes—mainly toto extendextend thethe chainchain for for one one of of the the functional functional groups groups to to reach reach a abinding binding site. site. Further, Further branching, branching of of alkyl alkyl chains chains results resultsin incompactness: compactness: thisthis feature will cause less disruption of the hydrogen-bondinghydrogen-bonding network of water. Consequently, the lipophilicity of the drug containing the branchedbranched alkylalkyl groupgroup willwill decrease, decrease, and and if if the the drug’s drug’s mechanism mechanism of of action action is relatedis related to toits its lipophilicity, lipophilicity, then then a significant a significant alteration alteration in thein the biologic biologic eff ecteffect will will ensue ensue [1]. [1]. CCycloalkylycloalkyl groupsgroups encountered encountered in drug in drug molecules molecules mostly mostly extend fromexten cyclopropyld from cyclopropyl to cyclohexyl. to cyclohexylIn drug design,. In drug cycloalkyl design, cycloalkyl groups are groups substituted are substituted for open-chain for open alkyl-chain groups alkyl gr tooups (i) betterto (i) better fill a fillhydrophobic a hydrophobic pocket inpocket a receptor, in a and receptor (ii) introduce, and (ii) rigidity introduce and limit rigidity the number and limit of conformations the number of a conformationsdrug molecule maya drug adopt. molecule Both emayffects adopt. contribute Both to effects attaining contribute more drug to attain affinitying and more selectivity drug affinity of the anddrug se containinglectivity of such the drug groups containing [2–4]. In monosubstitutedsuch groups [2–4] cyclohexyl. In monosubstituted groups—the cyclohexyl most common groups in— drugthe mostmolecules—metabolic common in drug hydroxylation molecules— ismetabolic stereoselective, hydroxylation favoring isthe stereoselective,trans isomer for favoring its higher the stability trans withisomer respect for its to higher the cis stabilityisomer (Figurewith respect1)[5]. to the cis isomer (Figure 1) [5].
Monosubstituted R cyclohexane
4-Hydroxylation 3-Hydroxylation
H OH
4 OH 4 H R + R R H + R OH 3 3 H H H OH H H trans-4-hydroxy cis-4-hydroxy trans-3-hydroxy cis-3-hydroxy
Figure 1. Stereoselective metabolic oxidation of monosubstituted cyclohexyl moiety.
Mechanism of Metabolic Oxidation of Alkyl Moieties Metabolic hydroxylation of alkyl groups is catalyzed by a family of monooxygenase enzymes, known as the “cytochrome P450” family, that contain heme redox centers. The heme group is Molecules 2020, 25, x FOR PEER REVIEW 3 of 29
Figure 1. Stereoselective metabolic oxidation of monosubstituted cyclohexyl moiety.
1.1. Mechanism of Metabolic Oxidation of Alkyl Moieties Molecules 2020, 25, 1937 3 of 29 Metabolic hydroxylation of alkyl groups is catalyzed by a family of monooxygenase enzymes, known as the “cytochrome P450” family, that contain heme redox centers. The heme group is characterizedcharacterized by an an iron iron atom atom coordinated coordinated to tothe the nitrogen nitrogen atoms atoms of four of four linked linked pyrrole pyrrole rings. rings. The Themechanism mechanism of metabolic of metabolic hydroxylation hydroxylation involves involves free free-radical-radical formation formation at the at thesubstrate substrate carbon carbon in the in thealkyl alkyl moiety, moiety, as asillustrated illustrated in inFigure Figure 22 [6[ –610–10]. ].In In drug drug molecules molecules containing containing more more than than one classclass ofof carboncarbon atoms,atoms, thethe prioritypriority ofof metabolicmetabolic hydroxylationhydroxylation isis dictateddictated byby thethe stabilitystability ofof thethe intermediateintermediate freefree radicals; radicals; however, however, anomalies anomalies may may occur occur due to due prevailing to prevailing electronic electronic or steric or eff stericects in effects the molecule. in the Duemolecule. to electronic Due to e ffelectronicects, the stabilityeffects, ofthe alkyl stability free radicalsof alkyl followsfree radicals this sequence: follows this benzyl, sequence: allyl > benzyl,3◦ > 2◦ >allyl1◦ > > methyl3° > 2° > [ 111° ].> methyl The diff [erent11]. The classes different of alkyl classes carbons of alkyl areshown carbons in are Figure shown1. in Figure 1.
Substrate carbon H abstraction of OH hydrogen FR . CH CH2 CH CH2 CH 2 CH Alkyl Alkyl free Alcohol 3+ . Fe2+OH 3+ Fe2+ substrate Fe O radical Fe OH CYP450 CYP450 CYP450 CYP450 Radical Activated Reduced initiator oxygen heme The radical initiator abstracts a hydrogen from the alkyl substrate to form a free radical.
3+ Fe O. Neutral oxygen radical derived FR: free radical from molecular oxygen CYP450 FigureFigure 2.2. Free-radicalFree-radical metabolicmetabolic alkylalkyl hydroxylationhydroxylation (adapted(adapted fromfrom [[33,,44]).]).
2.2. Data on SelectedSelected GroupsGroups ofof DrugsDrugs ContainingContaining AlkylAlkyl MoietiesMoieties TheThe selection selection of of drug drug candidates candidates for for metabolic metabolic alkyl-moiety alkyl-moiety hydroxylation hydroxylation and and carboxyl carboxyl functionalizationfunctionalization waswas basedbased onon thethe presencepresence ofof thethe groupsgroups inin TableTable1 .1.
2.1.2.1. NSAIDS TheThe chemicalchemical classificationclassification ofof NSAIDSNSAIDS isis givengiven inin thethe firstfirst partpart ofof thisthis reviewreview seriesseries [[1212].]. TheThe twotwo NSAIDSNSAIDS consideredconsidered inin thisthis section,section, ibuprofenibuprofen andand tolmetintolmetinare are ofof thethe arylalkanoic arylalkanoic acid acid class. class. 2.1.1. Ibuprofen 2.1.1. Ibuprofen Ibuprofen (Figure3) is an arylpropionic acid NSAID used in the management of arthritis as Ibuprofen (Figure 3) is an arylpropionic acid NSAID used in the management of arthritis as well well as for its analgesic and antipyretic properties. It acts as an NSAID by inhibiting COX and as for its analgesic and antipyretic properties. It acts as an NSAID by inhibiting COX and consequently PGE2, which is implicated in the inflammation process [13]. Ibuprofen is a chiral drug consequently PGE2, which is implicated in the inflammation process [13]. Ibuprofen is a chiral drug existing in two enantiomeric forms: S-(+) and R-( ). The NSAID activity of ibuprofen has been existing in two enantiomeric forms: S-(+) and R-(−−). The NSAID activity of ibuprofen has been reported to reside in the S-(+)-enantiomer [14–16], which is now marketed in a number of countries reported to reside in the S-(+)-enantiomer [14–16], which is now marketed in a number of countries as dexibuprofen; however, in most countries, the drug is used as the racemate. The possible reason as dexibuprofen; however, in most countries, the drug is used as the racemate. The possible reason why large pharmaceutical companies tend to market racemic equivalent ibuprofen is that the levo why large pharmaceutical companies tend to market racemic equivalent ibuprofen is that the levo enantiomer is metabolically converted in vivo to the dextro enantiomer [17]. The isobutyl group in enantiomer is metabolically converted in vivo to the dextro enantiomer [17]. The isobutyl group in ibuprofen contains three classes of carbon: two primary (C3, C3), one tertiary (C2), and one benzylic ibuprofen contains three classes of carbon: two primary (C3, C3), one tertiary (C2), and one benzylic (C1) (Figure3). As depicted in Figure4, phase I metabolic hydroxylation occurs at the three carbons (C1) (Figure 3). As depicted in Figure 4, phase I metabolic hydroxylation occurs at the three carbons to varying extents [17–22]. 3-Hydroxyibuprofen is further oxidized via the aldehyde intermediate to varying extents [17–22]. 3-Hydroxyibuprofen is further oxidized via the aldehyde intermediate to to the carboxylic acid metabolite. The benzylic-carbon oxidation results in the formation of a chiral the carboxylic acid metabolite. The benzylic-carbon oxidation results in the formation of a chiral secondary alcohol (1-hydroxyibuprofen). Both the intrinsic and the metabolically generated carboxyl secondary alcohol (1-hydroxyibuprofen). Both the intrinsic and the metabolically generated carboxyl groups are further metabolized in phase II to glucuronide conjugates. All the metabolites of ibuprofen groups are further metabolized in phase II to glucuronide conjugates. All the metabolites of ibuprofen are devoid of pharmacological activity [20,23]. are devoid of pharmacological activity [20,23].
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OH
R CH CH CH3 1-Hydroxyibuprofen 1 2 3 CH3 (minor) Isobutyl + OH
CH2 CH CH3 CYP2C9 O 1 2 3 R CH2 C CH3 2-Hydroxyibuprofen 1 2 3 CH3 HO CH3 (minor) R + CH3 Molecules 2020, 25, 1937 4 of 29 Ibuprofen R CH2 CH CH2OH 3-Hydroxyibuprofen 1 2 3 MoleculesMolecules 20202020,, 2255,, xx FORFOR PEERPEER REVIEWREVIEW (25%) 44 ofof 2929 Glucuronide CH3 conjugation at R CH2 CH CH2COOH COOH 1 2 3 OOHH CH3 RR CCHH CCHH CCHH33 11--HHyyddrrooxxyyiibbuupprrooffeenn Ibuprofen carboxy metabolite All1 1the m22etabo3l3ites are inactive. ((mmiinnoorr)) (37%) CCHH33 IIssoobbuuttyyll ++ Figure 3. Metabolism of ibuprofenOOHH. CCHH22 CCHH CCHH33 CCYYPP22CC99 OO 11 22 33 RR CCHH22 CC CCHH33 22--HHyyddrrooxxyyiibbuupprrooffeenn 11 22 33 CCHH33 2.1.2. TolmetinH HOO CCHH33 ((mmiinnoorr)) RR CCHH ++ Tolmetin (Figure3 34) is a pyrrole acetic acid NSAID. It is metabolized by the hydroxylation of the IIbbuupprrooffeenn RR CCHH22 CCHH CCHH22OOHH 33--HHyyddrrooxxyyiibbuupprrooffeenn 11 22 33 benzylic methyl group to the active hydroxymethyl derivative, which is further((2255%%)) oxidized to the GGlluuccuurroonniiddee CCHH33 inactive 5-ccpoo-nncarboxybenzoyljjuuggaattiioonn aatt RR -1C-CHmethylpyrroleH22 CCHH CCHH22CCOOOOHH-2-acetic acid in rat, monkey, and human [24,25]. Both CCOOOOHH 11 22 33 the intrinsic and metabolically producedCCHH33 carboxyl groups are further metabolized in phase II to the inactive glucuronide conjugates.IIbbuupprrooffeenn cc aar Therbbooxxy y retentionmmeettaabboolliittee of COXAA-linhibitinglll tthhee mmeettaabboo llii activitytteess aarree iinnaa cc byttiivve e.. the hydroxymethyl metabolite may indicate an auxiliary((3377%% ))pharmacophoric role of the benzylic methyl group, since the relatively large phenyl group is responsibleFigureFigure 3. 3. MetabolismMetabolism for the primary ofof ibuprofenibuprofen ibuprofen. pharmacophoric.. role.
2.12.1.2..2. TolmetinTolmetin CH3 Tolmetin TolmetinTolmetin (Figure(FigureHOOCCH2 44)) isisN aa pyrrolepyrrole aceticacetic acidacid NSAID.NSAID. ItIt isis metabolizedmetabolized byby thethe hydroxylationhydroxylation ofof thethe O benzylicbenzylic methyl methyl group group to toCH 3 the the active activeben z hydroxymethyly hydroxymethyllic-methyl derivative, derivative, which which is is further further oxidized oxidized to to the the R oxidation inactiveinactive 55--pp--carboxybenzoylcarboxybenzoyl--11--methylpyrrolemethylpyrrole--22--acetaceticic acidacid inin rat,rat, monkey,monkey, andand humanhuman [24,25[24,25].]. BothBoth CH OH COOH thethe intrinsicintrinsic andand metabolicallymetabolically producedproduced2 carboxylcarboxyl groupsgroups areare U furtherfurtherGT G lmetabolizedmetabolizeducuronide conjug a inintio n phasephase IIII toto thethe of both carboxyl groups inactiveinactive glucuronideglucuronide conjugates. conjugates.R The The retention retentionR of of COX COX--inhibitinginhibiting activity activity by by the the hydroxymethyl hydroxymethyl metabolitemetabolite mamayy indicateindicateT oananlm e auxiliaryauxiliarytin hydroxy mpharmacophoricpharmacophoricethyl Tolmetin c rolearolerbox yofof thethe benzylicbenzylic methylmethyl group,group, sincesince thethe relativelyrelatively largelarge phenylphenyl groupgroup m eisista bresponsibleresponsibleolite forfor the the m e primaryprimarytabolite pharmacophoricpharmacophoric role.role. (active) (inactive) CCHH Figure33 4. Metabolism of tolmetin. FigureTTooll 4.mmeeMetabolismttiinn of tolmetin.
HHOOOOCCCCHH22 NN 2.1.2.2.2. Sulfonylurea Tolmetin Oral AntidiabeticsOO CCHH33 bbeennzzyylliicc--mmeetthhyyll RR ooxxiiddaattiioonn TolmetinSulfonylurea (Figure oral4 )antidiabetics is a pyrrole have acetic the acid general NSAID. structure It is metabolized shown in Figure by the 5 hydroxylation, with the framed of CCHH OOHH CCOOOOHH themoiety benzylic representing methyl groupthe pharmacophore. to the active22 hydroxymethyl derivative,UUGGTT GG whichlluuccuurroonniid isdee c furthercoonnjjuuggaattiioonn oxidized to the ooff bbootthh ccaarrbbooxxyyll ggrroouuppss inactive 5-p-carboxybenzoyl-1-methylpyrrole-2-aceticRR RR acid in rat, monkey, and human [24,25]. Both the intrinsic and metabolically produced carboxyl groups are furtherH metabolized in phase II to the inactive TToollmmeettiinn hhyyddrrooxxOyymmeetthhOyyll TToollmmeettiinn ccaarrbbooxxyy N glucuronide conjugates. The mmee retentionttaabboolliittee of COX-inhibitingH mmeettaabbRoo1l:liitteeR3 activity by the hydroxymethyl metabolite R1 S N N R2 may indicate an auxiliary pharmacophoric((aaccttiivvee)) H role of(( theiinnaacct benzylictiivvee)) O methyl group, since the relatively large O p-beta-arylcarboxamidoethyl phenyl group is responsible for theFigureFigure primary 4.4. MetabolismMetabolism pharmacophoric ofof tolmetintolmetin role... Benzene sulfonylurea where R3 is aryl or 2.2. Sulfonylurea Oral Antidiabetics(Pharmacophore) heterocycle substituent 2.2.2.2. SulfonylureaSulfonylurea OralOral AAntidiabeticsntidiabetics SulfonylureaFigure 5. oral General antidiabetics structure of have sulfonylurea the general antidiabetics structure depicting shown the in Figurepharma5cophore, with the. framed SulfonylureaSulfonylurea oraloral antidiabeticsantidiabetics havehave thethe generalgeneral structurestructure shownshown inin FigureFigure 55,, withwith thethe framedframed moiety representing the pharmacophore. moietymoiety representingrepresenting thethe pharmacophore.pharmacophore. In the first-generation sulfonylureas in Figure 5, R1 is a small lipophilic group such as methyl or chloro, while R2 is a lipophilic alkyl or cycloalkyl group, mostly cyclohexyl. In the second-generation HH OO OO NN sulfonylureas, the alkyl and cycloalkyl substituents at R2 are mostly maintained while the substituent HH RR11:: RR33 RR11 SS NN NN RR22 at R1 is a large p-(β-arylcarboxyamidoethyl)HH group (Figure 5).OO This latter group enhances antidiabetic OO + activity through strong binding affinity to the ATP Kpp- -bchannelbeettaa--aarryyllcca ar[rb26booxx].aam mOniiddoo eethetthhyyl lother hand, according to
BBeennzzeennee ssuullffoonnyylluurreeaa wwhheerree RR33 iiss aarryyll oorr ((PPhhaarrmmaaccoopphhoorree)) hheetteerrooccyyccllee ssuubbssttiittuueenntt FigureFigure 5.5. GeneralGeneralGeneral structurestructure structure ofof sulfonylureasulfonylurea antidiabeticsantidiabetics depictingdepicting thethe pharmapharma pharmacophore.cophorecophore..
InIn thethe firstfirst first-generation--generationgeneration sulfonylureas sulfonylureas in in Figure Figure 5 55,R,, RR11 isisis aa a smallsmall small lipophiliclipophilic lipophilic groupgroup group suchsuch such asas methylmethyl oror chloro,chloro, while while R R22 isisis aa a lipophiliclipophilic lipophilic alkylalkyl alkyl oror or cycloalkylcycloalkyl cycloalkyl group,group, group, mostlymostly cyclohexyl.cyclohexyl. InIn In thethe the secondsecond second-generation--generationgeneration sulfonylureas,sulfonylureas, the the alkyl alkyl and and cycloalkyl cycloalkyl sub substituentssubstituentsstituents at at R R22 are areare mostlymostly mostly maintainedmaintained maintained whilewhile thethe substituentsubstituent atat RR11 isis aa largelarge pp--(β(β--arylcarboxyamidoethyl)arylcarboxyamidoethyl) groupgroup (Figure(Figure 55).). ThisThis latterlatter groupgroup enhancesenhances antidiabeticantidiabetic activityactivity throughthrough strongstrong bindingbinding affinityaffinity toto thethe ATPATP KK++ channelchannel [[2626].]. OnOn thethe otherother hand,hand, accordingaccording toto
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at R1 is a large p-(β-arylcarboxyamidoethyl) group (Figure5). This latter group enhances antidiabetic activity through strong binding affinity to the ATP K+ channel [26]. On the other hand, according Foye (2020) [26], the small lipophilic groups at R1 in the first-generation sulfonylureas have little to Foye (2020) [26], the small lipophilic groups at R in the first-generation sulfonylureas have little influence over activity. Hence, they may have been1 included to play auxiliary pharmacophoric or influence over activity. Hence, they may have been included to play auxiliary pharmacophoric or auxophoric roles. Nevertheless, only methyl groups at R1 are within the scope of this review. auxophoric roles. Nevertheless, only methyl groups at R are within the scope of this review. The first-generation sulfonylurea oral antidiabetics1 surveyed in this review include The first-generation sulfonylurea oral antidiabetics surveyed in this review include acetohexamide, acetohexamide, tolbutamide, chlorpropamide, and tolazamide, while the second-generation tolbutamide, chlorpropamide, and tolazamide, while the second-generation members include glyburide members include glyburide (glibenclamide), glimepiride, and glipizide [27]. (glibenclamide), glimepiride, and glipizide [27]. Mechanistically, the sulfonylurea antidiabetics act by binding to the specific receptor for Mechanistically, the sulfonylurea antidiabetics act by binding to the specific receptor for sulfonylureas on β-pancreatic cells, blocking the inflow of potassium (K+) through the ATP- sulfonylureas on β-pancreatic cells, blocking the inflow of potassium (K+) through the ATP-dependent dependent channel. The flow of K+ within the β-cell goes to zero; the cell membrane becomes channel. The flow of K+ within the β-cell goes to zero; the cell membrane becomes depolarized, depolarized, thus removing the electric screen, which prevents the diffusion of calcium into the thus removing the electric screen, which prevents the diffusion of calcium into the cytosol. The increased cytosol. The increased flow of calcium into β-cells causes contraction in the filaments of actomyosin flow of calcium into β-cells causes contraction in the filaments of actomyosin responsible for the responsible for the exocytosis of insulin, which is therefore promptly secreted in large amounts [28]. exocytosis of insulin, which is therefore promptly secreted in large amounts [28]. 2.2.1. Acetohexamide 2.2.1. Acetohexamide Acetohexamide (Figure 6) is metabolized by (i) reduction of the carbonyl group to give a Acetohexamide (Figure6) is metabolized by (i) reduction of the carbonyl group to give a hydroxy hydroxy metabolite that is 2.5 times as active as the parent drug, as well as (ii) stereoselective metabolite that is 2.5 times as active as the parent drug, as well as (ii) stereoselective oxidation of the oxidation of the cyclohexyl ring to trans-4′-hydroxyacetohexamide, which is inactive as an oral cyclohexyl ring to trans-4 -hydroxyacetohexamide, which is inactive as an oral antidiabetic [29,30]. antidiabetic [29,30]. 0
Acetohexamide O O O Carbonyl R' S reductase N N H H R' OH O R H 6' Hydroxyacetohexamide 5' OH 4' Major metabolite 2' (2.5-fold as active as R 1' 3' acetohexamide) 4'-trans-hydroxyacetohexamide (inactive) Figure 6. Metabolic pathways of acetohexamide.acetohexamide.
2.2.2. Tolbutamide Tolbutamide (Figure7 7)) is is primarily primarily metabolized metabolized byby benzylicbenzylic methylmethyl oxidationoxidation toto thethe primaryprimary alcoholic hydroxymethyl group, which is further oxidized to to the the carboxyl carboxyl group group (Figure (Figure 77)[) [31,3231,32].]. WhileWhile the the hydroxymethyl hydroxymethyl metabolite metabolite is equiactive equiactive with with tolbutamide, tolbutamide, the carboxy metabolite is inactive [[31].]. A minor route of tolbutamide metabolism occursoccurs viavia butylbutyl chainchain oxidationoxidation atat thethe ωω and ω--11 carbons to give primary and secondary alcohol metabolites, respectively, which have minimalminimal antidiabetic activityactivity (Figure(Figure7 ).7). An An inference inference can can be be made made from from the the ratio ratio of of the the hydroxy hydroxy metabolites metabolites of tolbutamide:of tolbutamide: when when a benzylic a benzylic methyl methyl group group and an and alkyl an chain alkyl are chain present are inpresent the same in the drug same molecule, drug themolecule, preference the preference of metabolic of oxidation metabolic is oxidation for the benzylic is for the methyl benzylic group. methyl Substantiation group. Substantiation of the inference of isthe given inference by the is highergiven by stability the higher of the stability benzylic of freethe benzylic radical involved free radical in the involved oxidation in the of theoxidation benzylic of methylthe benzylic group methyl compared group to thecompared alkyl-chain to the free alkyl radicals.-chain Thefree stabilityradicals. ofThe the stability benzylic of free the radicalbenzylic is duefree toradical resonance is due stabilization to resonance [33 stabilization], as depicted [33], in Figure as depicted8. The in metabolic Figure 8 oxidation. The metabolic of the benzylicoxidation methyl of the groupbenzylic occurs methyl as pergroup the occurs mechanism as per of the alkyl mechanism hydroxylation of alkyl shown hydroxylation in Figure2 shown. in Figure 2.
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O O O R'' R'' S CYP2C9 N N CH33 H H O O O HOOC HOCH22 H C R' R' 33 S R'' R :: p-Carboxyttollbuttamiide p-Hydroxymetthyll-CYP2C9 N N CH3 Tollbuttamiide H H ((60%,, iinacttiive)) HttoOllCbHu2ttamiide H C HOOC 3 CH OH (30%, equiactive) R' RR CH22OH : p-Carboxytolbutamide (p3-0H%y,d erqouxiyamcteivthey)l- Tolbutamide + (60%, inactive) tolbutamide Miinorr mettabolliittes ((<10%)) OH OHCH OH Gllucurroniide (30%, equiactive) off miiniimall acttiiviitty R 2 conjjugattiion R + CH33 Minor metabolites (<10%) OH Glucuronide of minimal activity conjugation R CH3 Figure 7.. Metabolic pathways of tolbutamide.. Figure 7. Metabolic pathways of tolbutamide. Figure 7. Metabolic pathways of tolbutamide.
CH CH CH CH2 .CH22 CH22 CH22 2 Benzyll free . . CH CH CH . radiicall .CH2 2 . 2 2 Benzyl free Resonanc.e forms of benzyll free .radiicall . radical . Figure 8. Resonance stabilization of the benzylic free radical radical... Resonance forms of benzyl free radical 2.2.3. Ch Chlorpropamidelorpropamide Figure 8. Resonance stabilization of the benzylic free radical. Chlorpropamide (Figure9) has been developed as a variant of tolbutamide in order to prolong 2.2.3.Chlorpropamide Chlorpropamide (Figure 9) has been developed as a variant of tolbutamide in order to prolong the drug’s antidiabetic effect effect with the consequent enhancement of potency. Ch Chlorpropamidelorpropamide is slowly metabolizedChlorpropamide by by alkyl-chain alkyl- (Figurechain oxidation oxidation 9) has atbeen the at developed theω and ω ω and-1 carbonsasω -a1 variant carbons to give of to tolbutamide primary give primary and in secondary order and secondaryto alcohols,prolong respectivelyalcohols,the drug’s respectively antidiabetic (Figure9)[ (Figure effect34]. with Both 9) [the metabolites34]. consequent Both metabolites have enhancement minimal have antidiabetic minimalof potency. antidiabetic activityChlorpropamide [20 activity]. It should is [20].slowly be It notedshouldmetabolized that be in noted chlorpropamideby alkyl that-chain in chlorpropamide oxidation metabolism, at the the m ω secondaryetabolism, and ω-1 alcohol carbons the secondary (55% to give of dose) alcoholprimary predominates (55% and secondary of dose) over thepredominatesalcohols, primary respectively alcohol over the (2%) (Figureprimary [34] (Figure 9 )alcohol [34].9). Both A(2%) possible metabolites [34] (Figure explanation have 9). A minimal possible of this finding antidiabeticexplanation resides activityof in this the finding higher [20]. It stabilityresidesshould in of be the noted intermediate higher that stability in secondary-propyl chlorpropamide of the intermediate free metabolism, radical secondary compared the-propyl secondary to the free primary-propyl radical alcohol compared (55% free of radical. to dose) the Inprimarypredominates the absence-propyl ofover free corresponding theradical. primary In the dataalcohol absence on metabolite(2%) of [corresponding34] (Figure concentrations, 9). dataA possible on the metabolite analogy explanation could concentrations, beof extendedthis finding the to theanalogyresides butyl incould group the be higher in extended tolbutamide stability to the (Section of butyl the intermediate group2.2.2). in tolbutamide secondary (Section-propyl 2 free.2.2)..2.2). radical compared to the primary-propyl free radical. In the absence of corresponding data on metabolite concentrations, the analogy could be extended to the butyl group in tolbutamide (Section 2.2.2). O O O 1 3 S 2 CH33 Chllorpropamiide N N H H O O O omega and omega--1 Cll 1 3 S 2 hCyHdr3roxCylhlalttoiiornp r opamide N RN + H H omega and omega-1 Cl CH hyCdHro33xylation CH22OH R R R + Botth mettabolliittes have + miiniimall anttiidiiabettiic acttiiviitty.. OH 3--Hydrroxy-- CH3 CH OH R2-Hydroxy- chllorrprropa2miide Both metabolites have 2-Hydroxy- + R chllorrprropamiide ((55%)) ((2%)) minimal antidiabetic activity. OH 3-Hydroxy- 2-Hydroxy- chlorpropamide Figure 9. Metabolism of chlorpropamide.. Figure 9. Metabolismchlo ofrpro chlorpropamide.pamide (55%) (2%) 2.2.4. Tolazamide Figure 9. Metabolism of chlorpropamide. Tolazamide (Figure 10) contains an azepane ring bonded to the terminal sulfonylurea nitrogen and 2.2.4.T Tolazamideolazamide (Figure 10) contains an azepane ring bonded to the terminal sulfonylurea nitrogen aand methyl a methyl group group bonded bonded to the to aromaticthe aromatic ring. ring. The The metabolism metabolism of tolazamide of tolazamide is depicted is depicted in Figurein Figure 12. The12. The azepaneTolazamide azepane ring ring(Figure is oxidized is oxidized 10) contains at position at position an 4 azepane0 to the4′ to 4 ring0thehydroxy 4′bonded hydrox group, toy thegroup, while terminal while the benzylic sulfonylurea the benzylic methyl nitrogen methyl group isgroupand oxidized a methylis oxidized sequentially group sequentially bonded to the to tothe hydroxymethyl the aromatic hydroxymethyl ring. and The carboxyl andmetabolism carboxyl groups of groups tolazamide [35]. [ It35]. is Itnoteworthyis is depicted noteworthy in that Figure that the concentrationsthe12. concentrationsThe azepane of ring the of twothe is oxidizedtwo alcoholic alcoholic at metabolites position metabolites 4′ are to almostarethe almost4′ hydrox equal, equal, whichy group, which leads while leads to the theto the inference benzylic inference thatmethyl that the benzylthegroup benzyl is and oxidized azepanyland az epasequentially freenyl radicals free radicals to arethe almost hydroxymethyl are almost of equal of stability. and equal carboxyl stability. However, groups However, as far [35]. as activityIt as is far noteworthy as is concerned, activity that is theconcerned,the hydroxymethylconcentrations the hydroxymethyl of metabolite the two alcoholic is equiactive metabolite metabolites with is equiactive the parentare almost with drug, equal, the while parent which the azepanyl drug, leads whileto alcohol the inference the metabolite azepanyl that isalcoholthe only benzyl weakly metabolite and active. az epa is only Furthermore,nyl free weakly radicals active. the carboxyare Furthermore, almost metabolite of equal the resulting stability. carboxy from metabolite However, the hydroxymethyl asresulting far as activity from group the is oxidationhydroxymethylconcerned, is theinactive. hydroxymethylgroup oxidation metaboliteis inactive. is equiactive with the parent drug, while the azepanyl alcohol metabolite is only weakly active. Furthermore, the carboxy metabolite resulting from the hydroxymethyl group oxidation is inactive.
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O O O O O N Tolazamide R' R' S O Tolazamide R' O NO O N N R' S H H Tolazamide R' N N N R' S H H HOOC HOCH2 H3C NR' N HOCH H C H RH HOOC 2 3 R' R HOOC HHyOdCroHx2 ytolazamide H3C Carboxytolazamide R' R C a r b o x (y1t7o%la)zamide H y d r o x(y3t5o%la)zamide N 4' OH Carboxytolazamide H y d r o x(3y5to%la)zamide R 4' OH ( i n(1a7ct%iv)e) (equiactive) N (17%) (35%) R N 4' OH (inactive) (equiactive) 4'-HydRroxymetabolite (31%) (inactive) (equiactive) 4'-Hyd(wroexaykm aecttaivbiotyli)te (31%) 4'-Hydroxymetabolite (31%) (weak activity) (weak activity) FigureFigure 10. 10. MetabolicMetabolic pathways of of tolazamide tolazamide.. Figure 10. Metabolic pathways of tolazamide. Figure 10. Metabolic pathways of tolazamide. 2.2.5.2.2.5. Glibenclamide Glibenclamide 2.2.5. Glibenclamide 2.2.5.GlibenclamideGlibenclamide Glibenclamide (also (also known known asas glyburide)glyburide) (Figure 1111)) is is a a second second-generation-generation sulfonylurea sulfonylurea oral oral Glibenclamide (also known as glyburide) (Figure 11) is a second-generation sulfonylurea oral antidiabetic.antidiabetic.Glibenclamide It contains It contains (also a cyclohexyl aknown cyclohexyl as group glyburide) group bonded bonded (Figure tothe to 1 1 terminal the) is terminala second nitrogen - nitrogengeneration of the of sulfonylurea sulfonylurea the sulfonylurea moiety.oral antidiabetic. It contains a cyclohexyl group bonded to the terminal nitrogen of the sulfonylurea Themoiety.ant cyclohexylidiabetic. The cyclohexyl ringIt contains forms ring the a cyclohexyl mainforms site the ofgroup main metabolism bondedsite of metabolism of to the the drug; terminal of it the is nitrogenstereoselectively drug; it ofis thestereoselectively sulfonylurea hydroxylated moiety. The cyclohexyl ring forms the main site of metabolism of the drug; it is stereoselectively tohydroxylatedmoiety. 3-cis and The 4- transcyclohexyl to 3-cisisomers and ring 4-trans (Figure forms isomers the11) main with(Figure site the 1 1of latter) with metabolism the isomer latter beingof isom theer thedrug; being major it the is major metabolitestereoselectively metabolite [36,37 ]. hydroxylated to 3-cis and 4-trans isomers (Figure 11) with the latter isomer being the major metabolite The[36,37hydroxylated two]. metabolites The two to 3metabolites-cis have and little 4-trans have hypoglycemic isomers little hypoglycemic (Figure effect 11) compared with effect the compared latter to the isom parent toer the being drug. parent the However, major drug. metaboliteHowever, retention [36,37]. The two metabolites have little hypoglycemic effect compared to the parent drug. However, ofretention 4-[36,37trans].-hydroxyglyburide The of 4two-trans metabolites-hydroxyglyburide may have prolong little may hypoglycemic theprolong hypoglycemic the effect hypoglycemic compared effect of effect to the the agentof parent the agent in thosedrug. in thoseHowever, with with severe retention of 4-trans-hydroxyglyburide may prolong the hypoglycemic effect of the agent in those with renalsevereretention impairment renal of 4im-transpairment [37-].hydroxyglyburide [37]. may prolong the hypoglycemic effect of the agent in those with severe renal impairment [37]. severe renal impairment [37]. O O O Glibenclamide S O O Glibenclamide O O S N O N O H H Glibenclamide O O S N N O O N O HN HN NH O H H HN R H Cl R Cl R Cl OH The hypoglycemic activity of both R OH + R R OH + Tmheeta hbyopliotegsly ics esmubics taacnttiivailtlyy olof wboerth + R mtThheatena hbthyoepli otpegaslr yeiscn ets mudbriucstg a.nctivalilty loofw beort h R4-trans-hydroxy R OH tmhaenta tbhoel ipteasr eins ts durbusgta.ntially lower 4-trans-hydroxy OH metabolite 3-cis-hydroOxHy than the parent drug. m4-ettraabnosl-ihteydroxy 3m-ectiasb-hoylidteroxy metabolite m3-ectiasb-ohlyidteroxy metabolite Figure 11. Metabolic pathways of glibenclamide. FigureFigure 11. 11. Metabolic pathways of glibenclamide. Figure 11.Metabolic Metabolic pathways of of glibenclamide glibenclamide.. 2.2.6. Glimepiride 2.2.6.2.2.6. Glimepiride Glimepiride 2.2.6.The Glimepiride cyclohexylmethyl group in glimepiride (Figure 12) allows the drug to exist in cis and trans TheThe cyclohexylmethyl cyclohexylmethyl group group inin glimepirideglimepiride (Figure 1 122)) allows allows the the drug drug to to exist exist in inciscis andand transtrans isomericThe forms;cyclohexylmethyl the active antidiabetic group in glimepiride form is the (Figuretrans isomer. 12) allows The latter the drug is metabolized, to exist in cisas shownand trans in isomericisomeric forms; forms; the the active active antidiabetic antidiabetic form form isis thethe trans isomer.isomer. The The latter latter is is metabolized, metabolized, as asshown shown in in Figureisomeric 12 forms;, through the the active sequential antidiabetic oxidation form ofis the cyclohexylmethyltrans isomer. The lattergroup is to metabolized, the hydroxymethyl as shown and in FigureFigure 12 1,2 through, through the the sequential sequential oxidation oxidation ofof thethe cyclohexylmethyl cyclohexylmethyl group group to to the the hydroxymethyl hydroxymethyl and and carboxyFigure 1 2 metabolites, through the [38,39 sequential]. The oxidation hydroxymethyl of the cyclohexylmethyl metabolite is an group active to the antidiabetic hydroxymethyl in animal and carboxycarboxy metabolites metabolites [38 [38,39,39]. The]. The hydroxymethyl hydroxymethyl metabolite metabolite is an is active an active antidiabetic antidiabetic in animal in animal models, modecarboxyls, while metabolites the carboxyl [38,39 metabolite]. The hydroxymethyl is inactive [3 9]. metabolite is an active antidiabetic in animal whilemode thels,carboxyl while the metabolite carboxyl metabolite is inactive is[ inactive39]. [39]. models, while the carboxyl metabolite is inactive [39].
O O O CH3 trans-Glimepiride O O O S CH3 trans-Glimepiride O O O S NO O N H H CH3 trans-Glimepiride O O S N N O N O N HN HN N NH H RH CYP2C9 N HN R CYP2C9 H R CYP2C9 CYP2C9 COOH R CYP2C9 CH2OH COOH R CH OH R CYP2C9 R 2 COOH CH OH trRans-Carboxy metabolite Rtrans-Hydroxymethy2 l trans-Carboxy metabolite t r a n sm-Hetyadbroolxityemethyl (devoid of hypoglycemic trans-Hydroxymethyl t(rdaenvso-iCda orfb ohxyyp omgelytacbeomliitce (3 3 % mase taacbtiovleit eas the parent activity) metabolite ( d e v o i d a octfi vhiytyp)oglycemic (d3r3u%g i nas a ancimtivael maso tdheel sp)a rent activity) d(3ru3g% i na sa nacimtivael maso tdheel sp) arent Figure 12. Metabolismdrug i nof a nglimepirideimal models) . Figure 12. Metabolism of glimepiride. FigureFigure 12. 12. MetabolismMetabolism of glimepiride glimepiride..
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2.2.7. Glipizide 2.2.7. Glipizide Glipizide (Figure 13) is a second-generation sulfonylurea with R2 in Figure6 as cyclohexyl Glipizide (Figure 13) is a second-generation sulfonylurea with R2 in Figure 6 as cyclohexyl substituent. It is metabolized by stereoselective hydroxylation to 4-trans and 4-cis-hydroxyglipizide [40]. substituent. It is metabolized by stereoselective hydroxylation to 4-trans and 4-cis-hydroxyglipizide No data are available on the activity of the hydroxy metabolites of glipizide. [40]. No data are available on the activity of the hydroxy metabolites of glipizide.
O O O Glibizide S O N N H H N N CYP2C9 H N R
OH R + R trans-4-hydroxy OH glipizide cis-3-hydroxy glipizide Figure 13.13. Metabolism of glipizide.glipizide.
2.3. Barbiturates BarbituratesBarbiturates are CNS depressants used as sedatives and hypnotics, anesthetics, and anti-seizureanti-seizure drugs. Barbiturates’ primary mechanism of action is inhibition of the central nervous system (CNS). (CNS). TheThe CNSCNS depressiondepression isis broughtbrought aboutabout byby stimulatingstimulating thethe inhibitoryinhibitory neurotransmitterneurotransmitter system in the brain called the gamma-aminobutyricgamma-aminobutyric acidacid (GABA)(GABA) system.system. The GABA channel is a chloride channel thatthat has has five five subunits subunits at itsat itsgate. gate. When When barbiturates barbiturates bind bind to the to GABA the GABA channel, channel, they cause they the cause chloride the ionchloride channel ion tochannel open, whichto open, allows which chloride allows ionschloride into ions the cellsinto inthe the cells brain. in the The brain. entry The of theentry chloride of the ionschloride into ions the brain into the leads brain to increased leads to increased negative charge negative and charge alteration and ofalteration the voltage of the across voltage the brainacross cells. the Thisbrain change cells. This in voltage change makes in voltage the brain makes cells the resistant brain cells to nerveresistant impulses, to nerve thus impulses depressing, thusthem depressing [41]. themMost [41]. barbiturates contain alkyl groups of varying lengths. Being lipophilic, these alkyl groups are functionalizedMost barbiturates by metabolic contain alkyl hydroxylation groups of atvarying different lengths. positions. Being The lipophilic, primary these alcohols alkyl resulting groups fromare functionalized oxidation of ωbycarbons metabolic are hydroxylation usually further at metabolizeddifferent positions. to carboxylic The primary acids. alcohols Amobarbital resulting and pentobarbitalfrom oxidation (Figures of ω carbons 14 and ar 15e, usually respectively) further are metabolized taken as representative to carboxylic examples acids. Amobarbital of barbiturates and thatpentobarbital contain alkyl (Figures groups. 14 and Amobarbital 15, respectively) has ethyl are and taken amyl as groupsrepresentative bonded examples to C5 of barbituricof barbiturates acid, whilethat contain pentobarbital alkyl groups. has ethyl Amobarbital and 2-methylbutyl has ethyl groupsand amyl bonded groups to C5bonded of barbituric to C5 of acidbarbitu (Figuresric acid, 14 andwhile 15 pentobarbital). Amobarbital has is ethyl metabolized and 2-methylbutyl by 30-hydoxylation groups bonded to give to 3 0C5-hydroxyamobarbital of barbituric acid (Figures as nearly 14 theand sole 15). metaboliteAmobarbital (Figure is metabolized 14)[42,43 ].by On 3′-hydoxylation the other hand, to thegive 2-methylbutyl 3′-hydroxyamobarbital group in pentobarbital as nearly the undergoessole metaboliteω and (Figureω-1 metabolic 14) [42,43]. oxidation On the othe to giver hand, primary- the 2-methylbutyl and secondary-alcohol group in pentobarbital metabolites, respectivelyundergoes ω (Figure and ω15-1)[ metabolic44]. The primary oxidation alcohol to give metabolite primary of- pentobarbital and secondary is further-alcohol oxidized metabolites, to the carboxylicrespectively acid. (Figure The three15) [4 metabolites4]. The primary of pentobarbital alcohol metabolite (the two of alcoholic pentobarbital metabolites is further and theoxidized carboxyl to metabolite)the carboxyli arec acid. further The conjugated three metabolites by glucuronic of pentobarbital acid in phase (the II two (Figure alcoholic 15)[44 metabolites]. The alcoholic and andthe thecarboxyl carboxylic metabolite) acid metabolites are further of conjugated pentobarbital, by glucuronic and their glucuronide acid in phase conjugates, II (Figure are 15 inactive) [44]. The as sedative-hypnoticsalcoholic and the carboxylic [44]. In contrast acid metabolites to the alcoholic of pentobarbital, metabolites of and pentobarbital, their glucuronide 30-hydroxyamobarbital conjugates, are hasinactive not been as sedative reported-hypnotics to undergo [4 glucuronide4]. In contrast conjugation—possibly to the alcoholic metabolites because, being of pentobarbital a tertiary alcohol,, 3′- ithydroxyamobarbital is sterically hindered has from not suchbeen areported metabolic to pathway.undergo glucuronide In addition toconjugation metabolism,—possibly redistribution because, of barbituratesbeing a tertiary has beenalcohol, reported it is sterically to play an hindered important from role such in their a metabolic deactivation pathway. [45]. RedistributionIn addition to ofmetabolism, the lipophilic redistribution barbiturates of from barbiturates the brain has to other been reportedbody compartments, to play an important such as adipose role in tissue, their willdeactivation lead to a reduction [45]. Redistribution of their effective of the concentration lipophilic barbiturates at the receptors from in the thebrain, brain thus to leadingother body to a losscompartments, of sedative-hypnotic such as adipose activity. tissue, On the will other lead hand, to a amobarbitalreduction of is their rapidly effective metabolized; concentration however, at the its extendedreceptors activity in the brain, has been thus attributed leading to the a loss 30-hydroxy of sedative metabolite,-hypnotic which activity. is present On the in other diminished hand, concentrationamobarbital is but rapidly is, nevertheless, metabolized; longer however, acting thanits extended the parent activity drug [43 has]. been attributed to the 3′- hydroxy metabolite, which is present in diminished concentration but is, nevertheless, longer acting than the parent drug [43].
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CH3 O CCHH33 CH 3 OO OO CH33 66 6 6 66 HN CH3 o HHNN11 55 CCHH33 3oo carbon oxidation HN 1 5 CH 3 1 5 33 ccaarrbboonn ooxxiiddaattiioonn HN11 55 CH33 4 4 OH 44 44 OOHH O 2 N 3 O O N O O 22 N33 O CH 3 OO 22 NN 3 OO CH H CH33 2 33 CCHH33 HH HH 3 AAmmoobbaarrbbiiitttaalll 3'-Hydroxyamobarbital 33''--HHyyddrrooxxyyaammoobbaarrbbiittaall FigureFigure 14. 14. MetabolicMetabolic pathway pathway of of amobarbital amobarbital.amobarbital...
OH OOHH oommeeggaa--11 ooxxiiiddaatttiiioonn O O OO OO oo 22o aalllccoohhoolll HN NH metabolite O O HHNN NNHH mmeettaabboolliittee OO OO 5 55 HN NH O HHNN NNHH O 1 CH 2OH 11 33 CH22OH O3 oommeeggaa ooxxiiiddaatttiiioonn OO O O OO OO Pentobarbital oo PPeennttoobbaarrbbiittaall 11o aalllccoohhoolll HN NH metabolite COOH HN NH mmeettaabboolliittee CCOOOOHH O O O O OO OO Caarrbbooxxyylliicc aacciidd Carboxylic acid HN NH meettaabboolliittee HHNN NNHH metabolite TThhee aalllccoohhoollliiicc aanndd ccaarrbbooxxyy mmeetttaabboollliiittteess O aarree gglluuccuurroonniiddee ccoonnjjuuggaatteedd iinn pphhaassee IIII.. O are glucuronide conjugated in phase II. FigureFigure 15. 15. MetabMetabMetabolicolicolic pathway pathway of of pentobarbital pentobarbital.pentobarbital...
2.4.2.4. MiscellaneousMiscellaneous 2.4.1. Valproic Acid 2.4.1.2.4.1. ValproicValproic AcidAcid Valproic acid (Figure 16) is an anticonvulsant drug used in the treatment of epilepsy. Its mechanism ValproicValproic acid acid (Figure (Figure 1 166)) is is an an anticonvulsant anticonvulsant drug drug used used in in the the treatment treatment of of epilepsy. epilepsy. Its Its of action involves the blockage of voltage-gated sodium channels and increased brain levels of mechanismmechanism ofof actionaction involvesinvolves thethe blockageblockage ofof voltagevoltage--gatedgated sodiumsodium channelschannels andand increasedincreased brainbrain gamma-aminobutyric acid (GABA) [46]. Valproic acid is mainly metabolized by oxidation to alkene levelslevels ofof gammagamma--aminobutyricaminobutyric acidacid (GABA)(GABA) [[4466].]. ValproicValproic acidacid isis mainlymainly metabolizedmetabolized byby oxidationoxidation and hydroxy products [47,48]. The two major hydroxy metabolites are the 4- and 5-isomers. The primary toto alkenealkene andand hydroxyhydroxy productsproducts [47,48[47,48].]. TheThe twotwo majormajor hydroxyhydroxy metabolitesmetabolites areare thethe 44-- andand 55--isomers.isomers. alcoholic metabolite (i.e., 5-hydroxyvalproic acid) is further oxidized to the carboxylic acid to give TheThe primaryprimary alcoholicalcoholic metabolitemetabolite (i.e.(i.e.,,, 55--hydroxyvalproichydroxyvalproic aacid)cid) isis furtherfurther oxidizedoxidized toto thethe carboxyliccarboxylic 2-n-propylglutaric acid (Figure 16). The substantial reduction in anticonvulsant activities of the valproic acidacid toto givegive 22--nn--propylglutaricpropylglutaric acidacid (Figure(Figure 1166).). TheThe substantialsubstantial reductionreduction inin anticonvulsantanticonvulsant activitiesactivities acid hydroxy and carboxy metabolites has been attributed to their increased molecular size and surface, ofof thethe valproicvalproic acidacid hydroxyhydroxy andand carboxycarboxy metabolitesmetabolites hashas beenbeen attributedattributed toto theirtheir increasedincreased molecularmolecular steric effects, and reduced log P, all of which are features that lower the extent of blood-brain barrier sizesize aandnd surface,surface, stericsteric effects,effects, andand reducedreduced loglog P,P, allall ofof whichwhich areare featuresfeatures thatthat lowerlower thethe extentextent ofof crossing [47,48]. bloodblood--brainbrain barrierbarrier crossingcrossing [47,48[47,48].].
C 3H 7 OH C3H7 C33H77 omega-1 OOHH CC33HH77 oommeeggaa--11 oxidation H3C 4 2 COOH ooxxiiddaattiioonn H C 4 2 COOH HH3CC 44 3 22 CCOOOOHH HH33CC 44 3 22 CCOOOOHH 3 5 33 1 3 5 33 1 55 11 55 11 Valproic acid VVaallpprrooiicc aacciidd 44--HHyyddrrooxxyyvvaalllpprrooiiicc aacciiidd omega oommeeggaa oxidation ooxxiiddaattiioonn C H CC3HH7 C3H7 33 77 CC33HH77 HOH C 4 2 COOH HOOC 4 2 COOH HHOOHH22CC 44 22 CCOOOOHH HOOC 44 3 22 COOH 25 33 1 HOOC5 33 C1 OOH 55 3 11 55 11 5-Hydroxyvalproic acid 2-n-Propylglutaric acid 55--HHyyddrrooxxyyvvaallpprrooiicc aacciidd 22--nn--PPrrooppyyllgglluuttaarriicc aacciidd FigureFigure 16. 16. MetabolicMetabolic pathways pathways of of valproic valproic acid acid.acid...
2.4.2.2.4.2. Risperidone/PaliperidoneRisperidone/Paliperidone Risperidone/Paliperidone RisperidRisperidoneRisperidoneone (Figure (Figure (Figure 17 1 1)77 blocks)) blocks blocks the the formationthe formation formation of serotonin of of serotonin serotonin and dopamine, and and dopamine, dopamine, thus decreasing thus thus decreasing decreasing psychotic psychoticandpsychotic aggressive andand aggressiveaggressive behavior. By behavior.behavior. targeting ByBy serotonin targetingtargeting 5HT2A serotoninserotonin and D25HT2A5HT2A receptors, andand D2D2 risperidone receptors,receptors, is risperidonerisperidone considered an isis consideredatypicalconsidered antipsychotic anan atypicalatypical drug antipsychoticantipsychotic and is used drugdrug in the andand treatment isis usedused ofinin schizophrenia.thethe treatmenttreatment ofof In schizschiz addition,ophrenia.ophrenia. it is used InIn addition,addition, off-label itit is is used used off off--labellabel in in the the treatment treatment of of ADHD ADHD in in children. children. The The metabolism metabolism of of risperidone risperidone is is stereoselectivelystereoselectively catalyzedcatalyzed (i)(i) byby CYP2D6CYP2D6 atat thethe aliphaticaliphatic heterocycleheterocycle toto givegive thethe majormajor enantiomerenantiomer
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in(+) the-9-hydroxyrisperidone, treatment of ADHD and in children. (ii) by CYP The3A4 metabolism to (−)-9-hydroxyrisperidone of risperidone is stereoselectively (Figure 17) [49– catalyzed53]. Both (+)(i)enantiomers- by9-hydroxyrisperidone,CYP2D6 are at the equiactive aliphatic and (ii) with heterocycle by risperidoneCYP3A4 to giveto (− and) the-9- hydroxyrisperidone major have enantiomer been developed ( +(Figure)-9-hydroxyrisperidone, into 17 ) the[49 –53 racemate]. Both enantiomersand (ii) by CYP3A4 are equiactive to ( )-9-hydroxyrisperidone with risperidone (Figure and have 17)[ 49 been–53]. developed Both enantiomers into the are equiactive racemate antipsychotic drug paliperidone− [49–53]. Almo and Lopez-Mufioz (2013) [51] have reviewed the antipsychoticwithclinical risperidone use drug of and bot paliperidone haveh risperidone been developed [49– 53 and]. Almo into paliperidone, the and racemate Lopez - antipsychoticMufioz stressing (2013) the drug [51 pharmacokinetic] paliperidone have reviewed [49 – and the53]. clinicalAlmopharmacodynamic and use Lopez-Mufioz of bot basesh (2013) risperidone on [51 which] have and the reviewed metabolite paliperidone, the clinical drug usestressing has of both been risperidonethe developed. pharmacokinetic and Further,paliperidone, and the pharmacodynamicstressingmetabolically the pharmacokinetic formed bases hydroxy on and whichgroup pharmacodynamic in the paliperidone metabolite has bases drug been on has whichesterified been the developed.with metabolite palmitic drug Further, acid has to beengive the metabolicallydeveloped.paliperidone Further, palmitate.formed the hydroxy metabolicallyPaliperidone group formedpalmitatein paliperidone hydroxy (Figure has group 17 been) is in a paliperidoneesterifieddepo-long with-acting has palmitic been injectable esterified acid prodrug to give with paliperipalmiticformulationdone acid indicatedpalmitate. to give paliperidone for Paliperidone a single palmitate.dose palmitate to be Paliperidonegiven (Figure once 1 monthly7) palmitate is a depo [53 (Figure-].long The-acting active 17) is injectable adrug depo-long-acting is released prodrug in formulationinjectablethe blood by prodrug indicated esterase formulation hydrolysis.for a single indicated dose to forbe given a single once dose monthly to be given [53]. The once active monthly drug [53 is]. released The active in thedrug bloodPaliperidone is released by esterase in palmitate the hydrolysis. blood is by an esterase example hydrolysis. of a prodrug that has been developed from a metabolite drug;PaliperidonePaliperidone hence, it can palmitate palmitatebe described is is an anas examplea example metabolite of of a a prodrug.prodrug prodrug Otherthat that has has metabolite been been developed developed prodrugs from from will abe a metabolite metabolite presented drug;drug;and discussed hence, hence, it it can canin due be be described describedcourse. as as a a metabolite metabolite prodrug. prodrug. Other Other metabolite metabolite prodrugs prodrugs will will be be presented presented andand discussed discussed in in due due course. course. N N F N Risperidone N F N Risperidone N O CYP2D6 O N O R CCYYPP23DA64 O N R CYP3A4 OH OCO(CH2)14CH3 N OH palmitic acid/H+ N OCO(CH ) CH * 2 14 3 N + N N palmitic acid/H N R esterase R * N esterase N 9-HydRroxyrisperidone (9HR) PalipReridone palmitoyl ester (Pa9li-pHeyriddroonxey, reisqpueiaricdtoivnee w(9itHhR 9)HR) Paliperid(oPnreo dpraulmg)itoyl ester (Paliperidone, equiactive with 9HR) (Prodrug) Figure 17. Metabolism and metabolite prodrug development of risperidone into paliperidone FigureFigurepalmitate 17. 17.. MetabolismMetabolism and and metabolite metabolite prodrug prodrug development development of risperidone of risperidone into paliperidone into paliperidone palmitate. palmitate. 2.4.3. Bupropion 2.4.3. Bupropion Bupropion (Figure (Figure 18 18) is) an is anatypical atypical antidepressant antidepressant drug drugused to used treat to major treat depressive major depressive disorder disorder(MDD)Bupropion and (MDD) seasonal (Figure and seasonal affective18) is an aatypicalff disorder;ective antidepressant disorder; it is also it is used drug also offused used-label to o fftreat -label as amajor smoking as a depressive smoking cessation cessationdisorder aid. (MDD)aid.Mechanistically, Mechanistically, and seasonal bupropion bupropion affective enhances enhances disorder; both both itnoradrenergic is noradrenergic also used and off and-dopaminergiclabel dopaminergic as a smoking neurotransmission neurotransmission cessation aid. via Mechanistically,viareuptake reuptake inhibition inhibition bupropion of the of thenorepinephrine enhances norepinephrine both and noradrenergic and dopamine dopamine transporters.and transporters. dopaminergic In addition, In addition,neurotransmission its itsmechanism mechanism via of reuptakeofaction action may inhibition may involve involve of the the the presynapticnorepinephrine presynaptic relea release andse ofdopamine of norepinephrine norepinephrine transporters. and and In dopamine. addition, Theits The mechanism major active of actionmetabolite may of involve bupropion the presynapticis hydroxybupropion release of (Figure norepinephrine 18)[) [54,5554,55 ]. and The dopamine. groups in this The metabolite major active are metabolitepositioned ofin in suchbupropion such a way a way asis hydroxybupropion to as allow to allow for the for occurrence the (Figure occurrence of 18 cyclization,) [54,55 of cyclization,]. The thus groups preventing thus in preventingthis further metabolite oxidation further are positionedofoxidation the hydroxymethyl of in the such hydroxymethyl a way group as to to group the allow carboxyl to for the the carboxyl group occurrence and group the of and consequent cyclization, the consequent loss thus of preventing activity.loss of activity. The further cyclic The oxidationmetabolitecyclic metabolite of is the an hydroxymethyl active is an active antidepressant antidepressant group [to55 ].the [carboxyl55]. group and the consequent loss of activity. The cyclic metabolite is an active antidepressant [55]. O H Cl O N H ca Cl N r r e bo 6 cdu n B arc y 2 re bt l P a R-Bupropion d oa Y 6 g n u sne C B e io c y 2 m t t l P o a a a gid n R-Bupropion s Y ex o e OH C mo ti o a H id x Cl OH N O o O H H HO Cl N Cl O N CH2OH O NH H HO Cl N CH OH NH 2 Threo/erythrohydro- Hydroxybupropion Cl Tphurperoo/peiroynthrohydro- Hydro(xaycbtiuvper)opion HydroCxlybupropion pupropion (active) Hydro(xaycbtiuvpe)ropion (active) Figure 18. Metabolic pathways of bupropion bupropion.. Figure 18. Metabolic pathways of bupropion. 2.4.4. Δ9-Tetrahydrocannabinol 2.4.4. Δ9-Tetrahydrocannabinol
Molecules 2020, 25, x FOR PEER REVIEW 11 of 29 Molecules 2020, 25, x FOR PEER REVIEW 11 of 29 Molecules 2020, 25, 1937 11 of 29
2.4.4. ∆9-Tetrahydrocannabinol
9 9 Δ∆9--TetrahydrocannabinolTetrahydrocannabinol (Δ (∆9-THC,-THC, Figure Figure 19 19) is) isthe the psychoactive psychoactive hallucinogenic hallucinogenic constituent constituent in Δ9-Tetrahydrocannabinol (Δ9-THC, Figure 19) is the psychoactive hallucinogenic constituent in Cannabisin Cannabis sativa sativa (hashish(hashish and and marijuana). marijuana). It contains It contains three three allylic allylic carbons carbons at positions at positions 11, 8, 11, and 8, and10a Cannabis sativa (hashish and marijuana). It contains three allylic carbons at positions 11, 8, and 10a 10a(Figure (Figure 19). 19 The). The allylic allylic positions positions at at C11and C11and C8 C8 are are metabolically metabolically hydroxylated, hydroxylated, with with the the former (Figure 19). The allylic positions at C11and C8 are metabolically hydroxylated, with the former hydroxylation resulting in the major equiactive hydroxymethyl metabolite; metabolite; due due to to steric steric hindrance, hindrance, hydroxylation resulting in the major equiactive hydroxymethyl metabolite; due to steric hindrance, position 10a 10a is is not not hydroxylated. hydroxylated. The The C11 hydroxymethylC11 hydroxymethyl metabolite metabolite is further is metabolically further metabolically oxidized position 10a is not hydroxylated.9 The C11 hydroxymethyl metabolite is further metabolically to the inactive 11-carboxy-∆ -THC metabolite9 (Figure 19)[56,57]. The resonance stabilization of the oxidized to the inactive 11-carboxy-Δ 9-THC metabolite (Figure 19) [56,57]. The resonance stabilization oxidized to the inactive9 11-carboxy-Δ -THC metabolite (Figure 19) [56,57]. The resonance stabilization ofallyl the free allyl radical free in radical∆ -THC in thatΔ9-THC accounts that foraccounts the formation for the of formation the major of allylic the major hydroxy allylic metabolite hydroxy is of the allyl free radical in Δ9-THC that accounts for the formation of the major allylic hydroxy metabolitedepicted in is Figure depicted 20. in Figure 20. metabolite is depicted in Figure 20.
CH OH CH2 OH CH3 2 CH3 OH HO 8 HO 8 9 10 OH (Delta-9-THC-11-OH) OH 10 OH (Delta-9-THC-11-OH) 9 1 (major, active) 7 1 (major, active) + 7 2 11CH 2 11 3 + 6 CH3 H3C O H C 6 9 H C n-C5H11 3 O 3 n-C H P2C 3H3C O n-C H H3HC C O 4 5 11 8 9 10 OH CY C9 H C 5 11 3 4 3 n-C5H11 10 OH YP2 3 H3C 8 9 1 C CYP3A4 7 CYP3A4 (Delta-9-THC-8-OH) 10a 1 2 7 2 COOH (Delta-9-THC-8-OH) 610a COOH (minor, inactive) H3C 6 (minor, inactive) H C O 3 n-C5H11 3H3C O 4 3 n-C H OH H C 4 5 11 OH 3 Diglucuronide Delta-9-tetrahydrcanabinnol Diglucuronide D e l t a -(9D-teelttraa-h9y-TdHrcCan)abinnol conjugate (Delta-9-THC) H C conjugate H3 C O n-C H 3H3C O n-C5 H11 H3C 5 11 9-THC-11-COOH (inactive) 9-THC-11-COOH (inactive) Figure 19. Metabolism of Δ9-tetrahydrocannabinol. FigureFigure 19.19. Metabolism of ∆Δ99--tetrahydrocannabinol.tetrahydrocannabinol.
CH . 2 CH2 CH2 CH2 CH2 H CH . 2 CH2 CH2 CH2 CH2 H H H . . H . . H ..
Allylic hydrogen Resonance structures contributing to the H Allylic hydrogen Resonance structures contributing to the H stability of the allyl free radical in THC stability of the allyl free radical in THC Figure 20. Resonance structures of the allyl free radicals in Δ9-THC. FigureFigure 20.20. Resonance structures of the allyl freefree radicalsradicals inin ∆Δ9-THC.-THC.
2.4.5. Tolterodine/Fesoterodine Tolterodine/Fesoterodine 2.4.5. Tolterodine/Fesoterodine Tolterodine (Figure 2121) is an antimuscarinic drug used in the treatment of overactive bladder Tolterodine (Figure 21) is an antimuscarinic drug used in the treatment of overactive bladder (OAB). As shown in Figure 2211, tolterodine is metabolized (i) through through mono mono-deisopropylation-deisopropylation to give (OAB). As shown in Figure 21, tolterodine is metabolized (i) through mono-deisopropylation to give an inactive metabolite, and (ii) through benzylic-methylbenzylic-methyl group oxidation to give 5-hydroxymethyl5-hydroxymethyl an inactive metabolite, and (ii) through benzylic-methyl group oxidation to give 5-hydroxymethyl tolterodine (5-HMT),(5-HMT), which is equiactive with the parent drugdrug [58–61]. Despite Despite being equiactive to its tolterodine (5-HMT), which is equiactive with the parent drug [58–61]. Despite being equiactive to its parent drug, 5-HMT5-HMT diddid notnot qualifyqualify forfor the the status status of of metabolite metabolite drug drug because because of of its its low low log log P valueP value of parent drug, 5-HMT did not qualify for the status of metabolite drug because of its low log P value of0.73 0.73 and and the the associated associated poor poor bioavailability bioavailability [ 58[58].]. However, However, the the problem problem waswas resolvedresolved by esterifying of 0.73 and the associated poor bioavailability [58]. However, the problem was resolved by esterifying the aroma aromatictic hydroxy (phenolic) group group with with isobutanoic isobutanoic acid acid to to produce produce the the prodrug prodrug fesoterodine, fesoterodine, the aromatic hydroxy (phenolic) group with isobutanoic acid to produce the prodrug fesoterodine, which has a log D7.4 valuevalue of of 5.7 5.7 [ [5858]] and and hence hence enjoys enjoys a a substantial substantial improvement improvement in in bioavailability. bioavailability. which has a log D7.4 value of 5.7 [58] and hence enjoys a substantial improvement in bioavailability. Fesoterodine is is the the second second example example of parent-drug of parent- equiactivedrug equiactive metabolites metab toolites have been to have developed been Fesoterodine is the second example of parent-drug equiactive metabolites to have been developedinto metabolite into metabolite prodrug. Theprodrug. first example The first from example this classfrom ofthis prodrugs class of isprodrugs paliperidone is paliperidone palmitate, developed into metabolite prodrug. The first example from this class of prodrugs is paliperidone palmitate,presented andpresented discussed and in discussed Section 2.4.2 in. Section Further 2 discussion.4.2. Further of metabolite discussion drugs of metabolite and prodrugs drugs will and be palmitate, presented and discussed in Section 2.4.2. Further discussion of metabolite drugs and prodrugsgiven in Section will be3 .given in Section 3. prodrugs will be given in Section 3.
Molecules 20202020, 2255, x 1937 FOR PEER REVIEW 1212 of of 29 Molecules 2020, 25, x FOR PEER REVIEW 12 of 29
O O OH OH O OH R OH + R O CYP2D6 isobutanoic acid/H R + R CYP2D6 isobutanoic acid/H N esterase N esterase R OH OH OH FesoterOoHdine TRolterodine 5-Hydroxymethyl- Fe(sloogt ePr o5d.7in) e CYP3A4 Tolterodine t5o-lHfeyrdordoixnye m(5e-tHhyMl-T) log P 1.81 (log P 5.7) CYP3A4 log P 1.81 tolfe(rlodg iPn e0 .(753-)HMT) N-desisopropyl tolterodine (eq(luoiga cPt i0v.e7 3w) ith N-desis(oinpraocptiyvle t)o lterodine t(oelqtueriaocdtiinveee w) ith tolterodinee) (inactive) Figure 21. Metabolic pathways of tolterodine and formation of fesoterodine. Figure 21. MetabolicMetabolic pathways pathways of tolterodine and formation of fesoterodine fesoterodine.. 2.4.6. Terfenadine/Fexofenadine 2.4.6. Terfenadine/ Terfenadine/Fexofenadine Terfenadine (Figure 22) is a second generation H1-antihistamine free of the sedative side effect associatedTerfenadine with (Figure the first 2222)- generation is a second generation H1-antihistamines. H1-antihistamineH1-antihistamine Terfenadine free of isthe almostsedative completely side effect effect metabolizedassociated with withby thebenzylic the first-generation first-methyl-generation-group H1-antihistamines. oxidation H1-antihistamines. to an Terfenadine equiactive Terfenadine iscarboxy almost metabolite, completelyis almost as metabolized completely shown in Figuremetabolizedby benzylic-methyl-group 22 [62 ],by and benzylic it is thus-methyl oxidation considered-group to a anoxidation prodrug. equiactive However,to an carboxy equiactive despite metabolite, carboxy this advantage, as metabolite, shown interfenadin Figure as shown 22e[ was62 in], withdrawnFigureand it is22 thus [62 from], considered and clinicalit is thus a use prodrug.considered because However, a ofprodrug. its cardiotoxic despite However, this effect advantage,despite [63 this]. Interfenadine advantage, the interim, wasterfenadin its withdrawn carboxye was metabolite,withdrawnfrom clinical being from use becausefree clinical of cardiotoxicity, of use its because cardiotoxic was of its edevelopedff ect cardiotoxic [63]. Ininto the effect a interim,drug [63 of]. its its In own carboxy the right interim, metabolite, under its the carboxy beingname ofmetabolite,free fexofenadine. of cardiotoxicity, being As free shown wasof cardiotoxicity, developedin Figure 24, into fexofenadinewas a developed drug of itsis amphotericinto own a rightdrug underandof its thus own the is name rightcapable under of fexofenadine.of existing the name as Asaof zwitterion fexofenadine. shown in at Figure physiologic As shown 24, fexofenadine in pH Figure [64]. 24,The is amphotericfexofenadine existence of and isfexofenadine amphoteric thus is capable andas zwitterion ofthus existing is capable at as physiologic a of zwitterion existing pH as at mayaphysiologic zwitterion be explained pHat physiologic [64 by]. Thethe existencecarboxylic pH [64 of]. group’s The fexofenadine existence interaction asof zwitterionfexofenadine with the atbasic physiologic as pyridzwitterioninyl pH n atitrogen may physiologic be via explained folded pH conformemayby the be carboxylicexplainedrs [65]. Generally, group’sby the carboxylic interaction zwitterions group’s with do not the interaction cross basic the pyridinyl withblood the-brain nitrogen basic barrier pyrid via inand foldedyl nhenceitrogen conformers do via not folded cause [65]. sedationconformeGenerally, [rs65 zwitterions [].6 5]. Generally, do not zwitterions cross the blood-brain do not cross barrier the blood and- hencebrain barrier do not causeand hence sedation do not [65 ].cause sedation [65]. pKa = 9.02 pKa = 9.02 metabolic oxidation omcectuarbso alitc t hoixsi dmaetitohnyl group N occurs at this methyl group N CYP3A4 OH OH CYP3A4 OH (almost 100%) pKa = 4.04 OH log P = 6.48 (almost 100%) pKa -= 4.04 log P = 6.48 pKa = 9.02 O - pKa = 9.02 O Terfenadine O O Terfenadine + NH NH OH Fexofenadine pharmacophore + OH OH F(Zewxoitfteenriaodnin aet pharmacophore OH p(ZHw 3it.5te-r7io.5n) at ploHg P3. =5- 27..851) log P = 2.81
Figure 2 22.2. Metabolism of terfenadine to fexofenadine fexofenadine.. Figure 22. Metabolism of terfenadine to fexofenadine. 2.4.7. Ebastine/Carebastine Ebastine/Carebastine 2.4.7. Ebastine/Carebastine Ebastine (Figure (Figure 23 2)3 is) isa second-generation a second-generation non-sedating non-sedating H1-antihistamine. H1-antihistamine. Its structure Its structure is similar is similarto thatEbastine of to terfenadine. that (Figure of terfenadine. 2 As3) in is the a second As latter in - drug, thegeneration latter in ebastine drug, non- sedating thein ebastine benzylic H1 - theantihistamine. methyl benzylic group methyl is Its metabolically structure group is metabolicallysimilaroxidized to to that the oxidized ofcarboxyl terfenadine. to groupthe carboxyl As after in an thegroup intermediate latter after drug, an step intermediate in ebastine in which the step hydroxymethyl benzylic in which methyl hydroxymethyl metabolite group is metabolimetabolicallyformed aste shownis formed oxidized in Figure as toshown the23. carboxyl Thein Figure resulting group 23. The metabolite, after resulting an intermediategiven metabolite, the name stepgiven of carebastine, in the which name hydroxymethyl of is carebastine, more active ismetabolithan more the activete parent is formed than drug the as and shownparent accounts indrug Figure for and nearly 2accounts3. The all resulting the for H1-antihistaminic nearly metabolite, all the H1 given activity-antihistaminic the [name66]. Despite of activity carebastine, its high[66]. Despiteislog more P value active its ofhigh than 6.9 log [67 the ], P ebastine parent value drug of does 6.9 and not [67 accounts cross], ebastine the for blood-brain doesnearly not all barrier,crtheoss H1 the- andantihistaminic blood accordingly-brain activity barrier, it does [ and66 not]. accordinglyDespitecause sedation. its high it does On log the not P other valuecause hand, sedation.of 6.9 carebastine, [67 On], ebastine the the other active does hand, metabolite not carebastine, cross of the ebastine, blood the active- existsbrain metabolite as barrier, zwitterion and of ebastine,accordinglyat physiologic exists it pH doesas zwitterion (Figure not cause 24 at) andphysiologic sedation. accordingly On pH the (Figure does other not 24) hand, cross and carebastine, theaccordingly blood-brain does the barrier. active not cross metabolite Further, the blood like of- brainebastine,terfenadine barrier. exists (Section Further,as zwitterion 2.4.6 like), ebastine at terfenadine physiologic is cardiotoxic (Section pH (Figure [68 2]..4. It 624)), is worth ebastineand accordingly mentioning is cardiotoxic does that, not despite [68 cross]. It carebastinethe is blood worth- mentioningbrainlack of barrier. cardiotoxicity that, Further, despite relative like carebastine to terfenadine its parent lack drug,of (Section cardiotoxicity it has 2.4. not6), been ebastinerelative developed to is its cardiotoxic parent into a drug, fully-fledged [68 it]. has It isnot drug worth been in developedmentioning intothat, despite a fully -carebastinefledged drug lack in of cardiotoxicity analogy with relative fexofenadine to its parent (Section drug, 2.4. it 6has). Almirallnot been- developed into a fully-fledged drug in analogy with fexofenadine (Section 2.4.6). Almirall-
Molecules 2020, 25, x FOR PEER REVIEW 13 of 29
Prodesfarma, a Spanish pharmaceutical company, reached stage III in the development of carebastine for the treatment of allergic conjunctivitis and allergic rhinitis, but the company subsequently discontinued the endeavor [69].
pKa = 8.19 CH2OH
N CYP3A4 N O O O O Ebastine Hydroxyebastine O log P = 6.9 CYP2I2 pKa = 3.5 CO-
+ N O O Carebasinte (major, equiactive) (zwitterion) Figure 23. Major pathway of ebastine metabolism.
2.5. Metabolic Conversion of Intrinsic Hydroxymethyl Groups in Parent Drugs to Active Carboxy Metabolites
MoleculesAs 2020has ,been25, 1937 shown in examples in Sections 2.1 through 2.4, carboxy-metabolites can result13 from of 29 the oxidation of ω-methyl groups in alkyl chains or methyl groups attached to cycloalkyl or aromatic Molecules 2020, 25, x FOR PEER REVIEW 13 of 29 rings. In all the cases cited, the carboxy metabolites were found to be pharmacologically inactive, that is,analogy they did with not fexofenadine give the same (Section pharm 2.4.6acological). Almirall-Prodesfarma, effect as the corresponding a Spanish pharmaceuticalparent drugs. However, company, Prodesfarma, a Spanish pharmaceutical company, reached stage III in the development of carebastine thisreached observation stage III in should the development not be generalized. of carebastine Three for the prominent treatment examples of allergic in conjunctivitis which intrinsic and for the treatment of allergic conjunctivitis and allergic rhinitis, but the company subsequently hydroxymethylallergic rhinitis, groups but the companyare metabolically subsequently oxidized discontinued to the carboxyl the endeavor groups [with69]. retention of activity discontinued the endeavor [69]. are hydroxyzine to cetirizine, salicin to salicylic acid, and losartan to losartan carboxylic acid.
pKa = 8.19 CH2OH 2.5.1. Hydroxyzine/Cetirizine
Hydroxyzine (FigureN 24) is a first-generationCYP3A4 H1-antihistamine.N H1-antihistamines are generally O O lipophilic in nature,O a property that causes them to cross theO blood-brain barrier to cause sedation as a main side effect [70E].b aHydroxyzinestine is primarily metabolized by oxidationHydroxyeb aofsti nthee primary alcoholic group to give the equiactive carboxyl metabolite (Figure 24) [O71]. Being appreciably more hydrophilic log P = 6.9 CYP2I2 pKa = 3.5 than hydroxyzine and capable of existing as a zwitterion at theCO- physiologic pH of 7.4 (Figure 24), the metabolite does not cross the blood-brain barrier and therefore does not cause sedation [72]. As a + result of this pharmacokinetic advantage, Nthe carboxy metabolite of hydroxyzine has been developed O into a second-generation H1-antihistamineO of its own right under the name of cetirizine [62,63]. The existence of cetirizine as zwitterion may be explained by analogy to fexofenadine in Section 2.4.6. Carebasinte Hydroxyzine and cetirizine are used concurrently( inma jclinicalor, equia csettings;tive) night urticaria may be a suitable (zwitterion) indication for the sedative hydroxyzine, while in allergic reactions demanding alertness, cetirizine is indicated [72]. Figure 23.23. Major pathway of ebastine metabolism metabolism..
2.5. Metabolic Conversion ofpK Intrinsica = 1.96 Hydroxymethylpharmacophore Groups in Parent DrugspKa to= 2 Active.19 Carboxy Metabolites As has been shown in examples in Sections 2.1 through 2.4, carboxy-metabolites can result from alcohol the oxidation of ω-methyl groups in alkyl chainsdehydrog oren amethylse groups attached to cycloalkyl or aromatic pKa = 7.4 N rings. In all the cases cited,N the carboxy metabolites were found to be pharmacologically inactive,- that N OH (45%) + NH O is, they didC lnot give the same pharmO acological effect as theCl corresponding parentO drugs. However, O this observationHy dr shouldoxyzine not be generalized.site of metaboli c Three prominent examples in which intrinsic oxidation Cetirizine hydroxymethyl logroupsg P = 3.1 are metabolically oxidized to the carboxyl groups with retention of activity (zwitterion at pH 3.5-7.5) log P = 1.5 are hydroxyzine to cetirizine, salicin to salicylic acid, and losartan to losartan carboxylic acid. pKa of the carboxyl group (COOH in cetirizine = 2.9.
2.5.1. Hydroxyzine/CetirizineFigure 24. Hydroxyzine metabolism to cetirizine.
2.5. MetabolicHydroxyzine Conversion (Figure of 2 Intrinsic4) is a first Hydroxymethyl-generation GroupsH1-antihistamine. in Parent Drugs H1-antihistamines to Active Carboxy are Metabolites generally lipophilic in nature, a property that causes them to cross the blood-brain barrier to cause sedation as a mainAs side has effect been shown[70]. Hydroxyzine in examples is inprimarily Sections metabolized 2.1–2.4, carboxy-metabolites by oxidation of the can primary result fromalcoholic the oxidationgroup to give of ω the-methyl equiactive groups carboxyl in alkyl metabolite chains or methyl (Figure groups 24) [71 attached]. Being appreciably to cycloalkyl more or aromatic hydrophilic rings. Inthan all hydroxyzine the cases cited, and the capable carboxy of existing metabolites as a zwitterion were found at tothe be physiologic pharmacologically pH of 7.4 inactive, (Figure 2 that4), the is, theymetabolite did not does give not the cross same the pharmacological blood-brain barrier effect asand the therefore corresponding does not parent cause drugs. sedation However, [72]. As this a observationresult of this shouldpharmacokinetic not be generalized. advantage, Three the carboxy prominent metabolite examples of inhydroxyzine which intrinsic has been hydroxymethyl developed groupsinto a second are metabolically-generation oxidizedH1-antihistamine to the carboxyl of its own groups right with un retentionder the name of activity of cetirizine are hydroxyzine [62,63]. The to cetirizine,existence of salicin cetirizine to salicylic as zwitterion acid, and may losartan be explained to losartan by carboxylic analogy to acid. fexofenadine in Section 2.4.6. Hydroxyzine and cetirizine are used concurrently in clinical settings; night urticaria may be a suitable 2.5.1. Hydroxyzine/Cetirizine indication for the sedative hydroxyzine, while in allergic reactions demanding alertness, cetirizine is indicatedHydroxyzine [72]. (Figure 24) is a first-generation H1-antihistamine. H1-antihistamines are generally lipophilic in nature, a property that causes them to cross the blood-brain barrier to cause sedation as a main side effect [70]. HydroxyzinepKa = 1.96 isp primarilyharmacophor metabolizede by oxidationpKa = 2 of.19 the primary alcoholic group to give the equiactive carboxyl metabolite (Figure 24)[71]. Being appreciably more hydrophilic than hydroxyzine and capable of existing as a zwitterion at the physiologic pH of 7.4 (Figure 24), the alcohol metabolite does not cross the blood-brain barrierdehydro andgena thereforese does not cause sedation [72]. As a result pKa = 7.4 N of this pharmacokineticN advantage, the carboxy metabolite of hydroxyzine has been developed- into a N OH (45%) + NH O second-generationCl H1-antihistamineO of its own right under theCl name of cetirizine [62O ,63]. The existence O of cetirizine as zwitterionHydroxyzine may be explainedsite of m byetab analogyolic to fexofenadine in Section 2.4.6. Hydroxyzine oxidation Cetirizine log P = 3.1 (zwitterion at pH 3.5-7.5) log P = 1.5 pKa of the carboxyl group (COOH in cetirizine = 2.9.
Molecules 2020, 25, x FOR PEER REVIEW 14 of 29 Molecules 2020, 25, 1937 14 of 29 and cetirizine are used concurrently in clinical settings; night urticaria may be a suitable indication for the sedative hydroxyzine, whileFigure in 2 allergic4. Hydroxyzine reactions metabolism demanding to cetirizine alertness,. cetirizine is indicated [72].
2.5.2.2.5.2. SalicinSalicin/Salicylic/Salicylic AcidAcid/Aspirin/Aspirin SalicinSalicin (Figure(Figure 2525)) isis aa naturalnatural productproduct foundfound inin thethe barkbark ofof thethe willowwillow tree.tree. TheThe majormajor turningturning pointpoint forfor salicylatesalicylate medicinesmedicines came in 1763,1763, whenwhen aa letterletter fromfrom thethe EnglishEnglish chaplainchaplain EdwardEdward StoneStone waswas readread atat aa meetingmeeting ofof thethe RoyalRoyal Society.Society. Stone’sStone’s letterletter describeddescribed thethe dramatic power of the willow barkbark extractextract toto curecure intermittentintermittent fever,fever, pain,pain, andand fatiguefatigue [[7373].]. AsAs shownshown inin FigureFigure 2525,, thethe metabolismmetabolism ofof salicinsalicin toto salicylicsalicylic acidacid involvesinvolves acetalicacetalic etherether bridgebridge hydrolysishydrolysis (reminiscent(reminiscent ofof aromatic-alkoxyaromatic-alkoxy dealkylation)dealkylation) toto a a phenolic phenolic group group as as well well as primaryas primary alcohol alcohol oxidation oxidation to the to carboxyl the carboxyl group. group. The latter The metaboliclatter metabolic pathway pathway is the subjectis the subject of this of section. this section.
1o benzylic alcohol oxidation
Salicylic acid OH COOH OH (in the GIT and blood stream) O OH O OH OH acetalic ether OH (CH3CO)2O bridge hydrolysis Salicin (in the lab then factory) COOH (alcoholic beta-glycoside in the willow bark) Aspirin OCOCH3 FigureFigure 25.25. Metabolic pathway of salicin.salicin.
ResearchResearch into willow bark extract culminated in 1899, when the German drug drug company, company, Bayer, preparedprepared aspirin by acetylating acetylating the the phenolic phenolic hydroxy hydroxy group group in in salicylic salicylic acid, acid, which which was was believed believed to tocause cause gastri gastricc irritation irritation and and bleeding bleeding [74]. [ 74However,]. However, subsequent subsequent research research has proven has proven that the that acetyl the acetylgroup groupin aspirin in aspirin is crucial is crucial to aspirin’s to aspirin’s mode mode of actionof action as as a aCOX COX inhibitor inhibitor in in the the treatment of of inflammation.inflammation. Through transacetylation, aspirinaspirin acetylatesacetylates thethe alcoholicalcoholic hydroxy groupgroup ofof thethe serineserine moietymoiety inin COX,COX, thusthus inhibitinginhibiting itit fromfrom catalyzingcatalyzing prostaglandinprostaglandin biosynthesisbiosynthesis [[7575].]. InIn additionaddition to to being being one one of of the the most most widely widely used used anti-inflammatory, anti-inflammatory, analgesic, analgesic, and antipyretic and antipyretic drug, aspirindrug, aspirin is now is renowned now renowned for its use for asits a use thrombolytic as a thrombolytic agent to agent prevent to prevent blood clotting blood inclotti patientsng in pronepatients to strokeprone [76 to – stroke78]. Furthermore, [76–78]. Furthermore, its preventive its role preventive in colorectal role cancer in colorectal has almost cancer been established has almost [79 been,80], andestablished it is now [79,80 being], activelyand it is researchednow being foractively other researched cancers [79 for,80 ].other cancers [79,80]. ThreeThree factors factors played playe significantd significant roles roles in the in design the design and development and development of aspirin: of (i)aspirin: nature, (i) by nature, providing by salicinprovidi fromng salicin the willow from bark;the willow (ii) metabolism, bark; (ii) metabolism, by converting by salicin conve torting salicylic salicin acid; to salicylicand (iii) medicinalacid; and chemistry,(iii) medicinal by blocking chemistry, the by phenolic blocking hydroxy the phenolic group of hydroxy salicylic group acid by of acetylation. salicylic acid Therefore, by acetylation. from a developmentalTherefore, from perspective, a developmental aspirin can perspective, be described aspirin as a natural-product-metabolite-synthetic can be described as a natural-product drug,- whilemetabolite salicin-synthetic can be considered drug, while a natural salicin prodrug. can be considered a natural prodrug.
2.5.3.2.5.3. LosartanLosartan/Losartan/Losartan Carboxylic AcidAcid LosartanLosartan (Figure(Figure 26 2)6) is is a selective,a selective, competitive competitive angiotensin angiotensin II receptor II receptor type type (AT1) (AT1) antagonist antagonist used asused antihypertensive. as antihypertensive. Through Through the route the shown route shown in Figure in 26 Figure, the 5-hydroxymethyl 26, the 5-hydroxymethyl group in group losartan in islosartan metabolized is metabolized by cytochrome by cytochrome P450 to the P450 5-carboxylic to the 5-carboxylic acid group acid through group intermediate through intermedi aldehydeate formationaldehyde formation [81–83]. This [81– metabolic83]. This metabolic route accounts route foraccounts 14% of for losartan 14% of dose; losartan the dose; remainder the remainder of the drug of isthe excreted drug is unchanged excreted unchanged [82,83]. The [82 carboxy,83]. The metabolite carboxy of metabolite losartan has of 10–40 losartan times has the 10 activity–40 times of the the parentactivity drug of the [82 parent,83]. Since drug losartan [82,83]. is Since only losartan partially is converted only partially into an converted active form, into it an is notactive considered form, it is a typicalnot considered prodrug. a typical prodrug.
Molecules 2020, 25, 1937 15 of 29 MoleculesMolecules 20202020,, 2255,, xx FORFOR PEERPEER REVIEWREVIEW 1515 ofof 2929
HH HH OOHH NN NN NN NN OOHHCC NN NN NN NN 55 11 NN CCYYPP22CC99 NN CCll CCll 44 22 NN NN 33 4 AA4 P33 YYP LLoossaarrttaann CC LLoossaarrttaann HH NN NN aallddeehhyyddee HHOOOOCC NN NN 55 11 NN CCll AAccttiivvee ccaarrbbooxxyylliicc 44 22 aacciidd mmeettaabboolliittee NN 33
FigureFigure 26 26.26.. MetabolismMetabolism ofof losartanlosartan losartan...
AccordingAccording to to Foye Foye [ [881811],], the the hydroxymethyl hydroxymethyl group group in in losartan losartan can can be be replaced replaced by by other other groups groups includingincluding ca carboxy,carboxy,rboxy, keto,keto, or or benzimidazole, benzimidazole, to to givegive activeactive ARBARB drugs. drugs. Such Such groups groups interact interact with with the the ATAT11 receptorreceptor via via either either ionic, ionic, ion-dipole,ion ion--dipole,dipole, or or dipole-dipoledipole dipole--dipoledipole bindings. bindings. The The considerable considerable increase increase in in activityactivity of of the the carboxy carboxy metabolite metabolite ofof losartanlosartan comparedcompared toto thethe parentparent drug drug may may be be explained explained by by the the metabolite’smetabolite’s increasedincreased a affinityaffinityffinity to toto the thethe receptor receptorreceptor caused causedcaused by byby the thethe stronger strongerstronger ion-ion ionion--ionion or ion-dipole oror ionion--dipoledipole binding bindingbinding due duetodue the toto ionizedthethe ionizedionized carboxylate carboxylatecarboxylate group groupgroup at physiologic atat physiologicphysiologic pH pH comparedpH comparedcompared to the toto the hydrogenthe hydrogenhydrogen bond bondbond binding bindingbinding of the ofof thehydroxylthe hydroxylhydroxyl group groupgroup in the inin the parentthe parepare drug.ntnt drug.drug.
2.6.2.6. MetabolicMetabolic OxidationOxidation ofof MethyleneMethylene GroupsGroups Alpha Alpha ( (αα)) to to Carbonyl Carbonyl and and Imino Imino Groups Groups Generally,Generally, methylene methylene groups groups alpha alpha to to carbonyl carbonyl as as well well as as imino imino groups groups undergo undergo metabolic metabolic oxidationoxidation via via mixed mixed function function oxidases oxidases [84,85 [[84,8584,85].]. ExamplesExamples ofof drugsdrugs inin whichwhich ss suchuchuch groupsgroups areare foundfound areare diazepamdiazepam and and alprazolamalprazolam withinwithin thethe benzodiazepinebenzodiazepine class,class, whosewhose membersmembers areare usedused used asas as tranquilizers,tranquilizers, tranquilizers, hypnotics,hypnotics, or or anticonvulsants. anticonvulsants. TheThe The mechanismmechanism mechanism ofof of metabolicmetabolic metabolic oxidationoxidation oxidation involves,involves, involves, asas as aa a firstfirst first step, step, the the formationformation of of a a resonance resonance-stabilizedresonance--stabilizestabilizedd free radical, as depicted in Figure 227277... AA hydroxylhydroxyl groupgroup will will then then bebe transferred transferred to to to the the the free free free radical radical radical in accordancein in accordance accordance with with with the mechanism the the mechanism mechanism of metabolic of of metabolic metabolic alkyl oxidation alkyl alkyl oxidation oxidation shown showninshown Figure inin 2 FigureFigure. 22..
BBeennzzooddiiaazzeeppiinnee RR RR RR OO.. OO OO 11NN NN NN 22 .. 33 33 NN CCll 77 NN CCll NN CCll 66 55 44 RR OO NN 33 MMeetthhyylleennee ggrroouupp CCll .. NN aallpphhaa ttoo tthhee ccaarrbboonnyyll aanndd iimmiinnoo ggrroouuppss
RReessoonnaannccee ffoorrmmss ccoonnttrriibbuuttiinngg ttoo tthhee ssttaabbiilliittyy ooff tthhee bbeennzzooddiiaazzeeppiinnee ffrreeee rraaddiiccaall FigureFigure 27 27.27.. ResonanceResonance stabilizationstabilization ofof tt thehehe benzodiazepinebenzodiazepine free free radical radical.radical..
2.6.1.2.6.1. DiazepamDiazepam AsAs shown shown in in FigureFigure 28 2828,,, diazepam diazepamdiazepam is isis mainly mainlymainly metabolized metabolizedmetabolized by byby hydroxylation hydroxylationhydroxylation at atat the thethe carbon carboncarbon atom atomatomα toαα totheto thethe carbonyl carbonylcarbonyl and andand imino iminoimino groups groupsgroups at position atat positionposition 3, as 3, well3, asas aswellwell by asasN -dealkylation byby NN--dealkylationdealkylation [86–88 [[].8686 Both––8888].]. metabolic BothBoth metabolicmetabolic routes routesgiveroutes equiactive givegive equequ productsiactiveiactive productsproducts with respect withwith torespectrespect diazepam, toto diazepamdiazepam though with,, thoughthough modified withwith pharmacokineticmodifiedmodified pharmacopharmaco propertieskinetickinetic propertiesthatproperties affect thethatthat drugs’ affect affect duration the the drugs’ drugs’ of action. duration duration Both of hydroxylationof action. action. Both Both at hydroxylationposition hydroxylation 3 and N at at-dealkylation position position 3 3 resultand and NN in-- dealkylationdealkylation resultresult inin increasedincreased metabolitemetabolite polaritypolarity andand hencehence enhancedenhanced metabolitemetabolite elimination.elimination. InIn
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MoleculesMolecules 20202020,, 2255,, xx FORFOR PEERPEER REVIEWREVIEW 1616 ofof 2929 increased metabolite polarity and hence enhanced metabolite elimination. In addition, glucuronide addition,conjugationaddition, glucuronideglucuronide taking place conjugationconjugation at the metabolically takingtaking placeplace generated atat thethe metabolicallymetabolically hydroxy group generatedgenerated results hydroxy inhydroxy fast elimination groupgroup resultsresults and indeactivationin fastfast eliminationelimination of the andand metabolites. deactivationdeactivation ofof thethe metabolites.metabolites.
HH OO NN NNoorrddaazzeeppaamm
CCll NN A44 C 3A CYYP3 CH YPP3 P3AA4 CH33 CCY 199 4 2CC1 H 9 OO YPP2 H OO 9 NN CCY NN 8 1 8 1 OH 33 * OH C * 33 Cl N CYYP CH Cl NN Cl 7 N P 3A CH33 Cl 7 6 55 3A 4 6 4 OO N 4 N P3AA4 CYYP3 OH C 9 ** 3 OH 2C119 3 YPP2C CCll NN CCY DDiiaazzaaeeppaamm OOxxaazzeeppaamm TTeemmaazzeeppaamm
TThhee tthhrreeee ddiiaazzeeppaamm mmeettaabboolliitteess aarree pphhaarrmmaaccoollooggiiccaallllyy aaccttiivvee,, tthhoouugghh wwiitthh ddiiffffeerreenntt dduurraattiioonnss.. BBootthh ooxxaazzeeppaamm aanndd tteemmaazzeeppaamm aarree ffuurrtthheerr mmeettaabboolliizzeedd iinn pphhaassee IIII ((aatt tthhee 33--OOHH ggrroouupp)) ttoo tthhee gglluuccuurroonniiddee ccoonnjjuuggaatteess,, wwhhiicchh aarree iinnaaccttiivvee.. .. FigureFigure 28. 28. MetabolicMetabolic pathwayspathways ofof diazepamdiazepam diazepam...
TheThe meta metabolicmetabolicbolic hydroxylation hydroxylation of of diazepam diazepam at at position position 3 3 results results in in the the generation generation of of chiral chiral centers centers inin both both temazepamtemazepamtemazepam and andand oxazepam oxazepamoxazepam (Figure (Figure(Figure 28 22).88).). However, However,However, despite despitedespite the thethe presence presencepresence of severalofof severalseveral reports reportsreports in the inin theliteraturethe literatureliterature describing describingdescribing the the separationthe separationseparation of the ofof the enantiomersthe enantiomersenantiomers of the ofof the drugsthe drudru [gs89gs – [89[8992],––9292 studies],], studiesstudies investigating investigatinginvestigating the theactivitythe activityactivity of their ofof thethe separatediirr separatedseparated enantiomers enantiomersenantiomers are lacking.areare lacking.lacking.
2.6.2.2.6.2. AlprazolamAlprazolam TheThe triazolobenzodiazepine triazolobenzodiazepine alprazolam alprazolam (Figure (Figure 2929)) is is metabolized metabolized (i) (i) by by hepatic hepatic microsomal microsomal oxidationoxidation atat C4, C4, which which is is alpha alpha to to two two imino imino moieties, moieties, t totoo give give 4 4-hydroxyalprazolam,4--hydroxyalprazolam,hydroxyalprazolam, andand (ii)(ii) at at the the α methylmethyl group group at at positionposition 1 1 toto givegive αα---hydroxyalprazolamhydroxyalprazolamhydroxyalprazolam (Figure 29).). BothBoth Both metabolitesmetabolites metabolites havehave have decreaseddecreased decreased benzodiazepinebenzodiazepine receptor receptor affinity aaffinityffinity comparedcompared toto thethe parentparent drugdrugdrug [[[939393].].].
aallllyylliicc methyl 22 methyl H C 1 H3C N H33C 1 NN H3C N HOCH2 N N 3 HOCH2 N NN 10 N 3 N N 10 NN N N CYPIIIA 9 PIIIA N 4 CYPIIIA 9 CCYYPIIIA N 4 OH subfamily 44 mily ** OH subfamily 6 ssuubbffaamily N Cl 6 N CCll N Cl 88 N Cl N 77 55 Cl N
44--HHyyddrrooxxyyaallpprraazzoollaamm Alprazolam Alprazolam aallpphhaa--HHyyddrrooxxyyaallpprraazzoollaamm Figure 29. Metabolic pathways of alprazolam. Figure 29. MeMetabolictabolic pathways pathways of of alprazolam alprazolam..
2.7.2.7. AA Alkyl-Moietylkyllkyl--MMoietyoiety MM Metabolicetabolicetabolic HH Hydroxylationydroxylationydroxylation in in P ProdrugProdrugrodrug A ActivationActivationctivation
2.7.1.2.7.1. OxazaphosphorinesOxazaphosphorines MetabolicMetabolic alkyl alkyl alkyl-moiety--moietymoiety hydroxylation hydroxylation hydroxylation in in in prodrug prodrug prodrug activation activation activation is is best best is best exemplified exemplified exemplified by by the the by three three the oxazaphosphorinethreeoxazaphosphorine oxazaphosphorine alkylatingalkylating alkylating antianticancercancer anticancer prodprodrugsrugs,, prodrugs,cyclophosphamide,cyclophosphamide, cyclophosphamide, ifosfamideifosfamide,, andand ifosfamide, profosfamideprofosfamide and [94,95profosfamide[94,95].]. TheThe metabolicmetabolic [94,95]. andand The chemicalchemical metabolic processesprocesses and chemical thatthat leadlead processes toto thethe activationactivation that lead ofof to thethe the threethree activation drugsdrugs inin of vivovivo the arethreeare respectivelyrespectively drugs in vivo illustratedillustratedare respectively inin FigFiguresures illustrated3300––3322.. TheThe infirstfirst Figures stepstep inin 30 thethe–32 activationactivation. The first processprocess step in isis thethethe activationmetabolmetabolicic hydroxylationprocesshydroxylation is the metabolic ofof thethe 44--methylenemethylene hydroxylation groupgroup of the ofof the 4-methylenethe commoncommon groupstructuralstructural of the feature,feature, common thethe structural cyclophoscyclophos feature,phphamide.amide. the α Generally,cyclophosphamide.Generally, carbonscarbons αα Generally, toto heteroatomsheteroatoms carbons inin heterocyclesheterocyclesto heteroatoms areare activatedactivated in heterocycles byby metabolicmetabolic are activated oxidationoxidation by [[ metabolic9696]].. Next,Next, thethe secondarysecondary alcoholalcohol soso producedproduced willwill tautomerizetautomerize toto thethe aldehydicaldehydic groupgroup toto givegive thethe aldoaldo tautomer.tautomer. ThisThis is is followed followed by by spontaneousspontaneous nonnon--enzymicenzymic elimination elimination ofof thethe aldehydic aldehydic neutral neutral fragment, fragment, acrolein,acrolein, toto give give the the active active alkylating alkylating agent,agent, thethe nitrogen nitrogen mustard. mustard. AcroleinAcrolein causes causes hemorrhagic hemorrhagic
Molecules 2020, 25, 1937 17 of 29
oxidation [96]. Next, the secondary alcohol so produced will tautomerize to the aldehydic group to MoleculesgiveMolecules the 20 2020 aldo202020,, , 2 22555 tautomer.,, , x xx FOR FORFOR PEER PEERPEER This REVIEW REVIEWREVIEW is followed by spontaneous non-enzymic elimination of the aldehydic171717 ofofof 292929 neutral fragment, acrolein, to give the active alkylating agent, the nitrogen mustard. Acrolein causes hemorrhagic cystitis, an adverse effect that can be offset by the concurrent administration of mesna. cystiticystitis,s,s, an an an adverse adverse adverse eff eff effectect that that can can be be offset offset by by the the concurrent concurrent administration administration of of mesna. mesna. TheThe The mechanism of action of mesna involves the formation of a highly water-soluble conjugate of mechanismmechanism of of action action of of mesna mesna involves involves the the formation formation of of a a highly highly water water---solublesolublesoluble conjugate conjugateconjugate of ofof acrolein acrolein acrolein that is excreted in the urine [97] (Figure 33). thatthatthat isisis excretedexcretedexcreted ininin thethethe urineurineurine [9[9[977]]] (((FigureFigure 33)33)...
Cl CCll CCClll CCll CCll
O O N OO N OO NN O NN NN PP PPP PPP P CCYPP33A44 O NH TTaauuttoomeerriizzaattiioonn O NH OO11 33NNHH CYP3A4 OO111 333NNHH Cl Tautomerization O NH CCll 1 3 CCClll CCll CCll 44 444 CCHO 66 4 666 CCHHOO 6 OOHH 55 55 5 5 AAllddldoooppphhhooosssppphhhaaammiididdeee CCyyycccllolooppphhhooosspspphhhaaammiiddideee 444--H-Hyyydddrrorooxxxyyy--C-CPPP Cl (CP) CCll ((CCPP)) SSSpppooonnnttataannneeeooouuusss e eelliilmimiininnaaattitioioonnn O (( n(nnooonnn---eeennnzzzyyymmiicicc))) OO NN HH22CCC CCCHH CCHO ++ 2 CHO + PPP Accrroolleeiinn HHOO NNHH22 Acrolein 2 CCClll ((Urroottooxxiicciittyy)) (Urotoxicity) PPPhhhooosssppphhhaaammiididdeee m muuusssttataarrdrdd ((A(Acccttitivivveee a aallklkkyyyllalaattitinninggg a aagggeeennntt)t)) FigurFigureFiguree 30 30.30.. . Metabolic Metabolic activation activation of of cyclophosphamide cyclophosphamide by by the the the 4 4 4-methylene-group4---methylenemethylene---groupgroup hydroxylation hydroxylation.hydroxylation.. .
CCll CCll CCll Cl CCClll O O NH O NNHH O NNHH OO NH P Cl NH PPP CCClll CCCYYPPP333AA444 PP CCll TTaauuttoomeerriizzaattiioonn PP CCll O 33N O 11 33N Tautomerization P Cl O111 33N O11 33N OO NN 444 66 444 666 6 CCHO OOHH CHO 555 555 IIfIfofoosssffafaammiididdeee 444--H-Hyyydddrrorooxxxyyyiiffiofoosssffafaammiididdeee AAllddldoooiififofoosssffafaammiididdeee
CCClll SSSpppooonnnttataannneeeooouuusss e eelliilmimiininnaaattitioioonnn (( n(nnooonnn---eeennnzzzyyymmiicicc))) H CC CCH CCHO OO NH HH222CC CCHH CCHHOO +++ NH Accrroolleeiinn PPP CCClll Acrolein HHOO NN ((U(Urroroottotooxxxiicicciittiytyy))) HH IIfIfofoosssffafaammiididdeee m muuusssttataarrdrdd ((A(Acccttitivivveee a aallklkkyyyllalaattitinninggg a aagggeeennntt)t)) FigureFigure 31 31.31.. . Metabolic Metabolic activation activation of of ifosfamide ifosfamide by by the the the 4 4 4-methylene4---methylenemethylene group groupgroup hydroxylation hydroxylation.hydroxylation.. .
CCll CCll CCll CCll CCClll
OO N CCClll OO N CCClll O CCll NN NN OO NN Cl PPP CCYPP33A44 PPP TTaauuttoomeerriizzaattiioonn PP O N CCClll CCYYPP33AA44 O N CCClll Tautomerization PP CCll OO111 333NN OO111 333NN OO NN Cl 44 44 66 44 44 66 666 CCCHHOO OOHH 555 555 TTrrooffoossffaamiiddee TTroroffoossffaammididee 444--H-Hyyydddrrorooxxxyyyrrorooffofoossfsfafaammiididdeee AAllddldooottrrtorooffofoossfsfafaammiididdeee SSppoonnttaanneeoouuss eelliimiinnaattiioonn CCClll SSppoonntatanneeoouuss e elilimmininaattioionn (( n(nnooonnn---eeennnzzzyyymmiicicc))) CCll OO N CCll H2CC CCH CCHO ++ N H22C CH CCHHOO ++ PP PP CCll AAccrcroroolleleieininn HHOO NN Cl ((Urroottooxxiicciittyy)) ((UUrroototoxxicicitiyty)) TTTrrorooffofoossfsfafaammiididdee e m muuusssttataarrdrdd ((A(Acccttiitvivveee a aallklkkyyyllalaattiitnninggg a aagggeenenntt))t) FigureFigure 32 32.32.. . Metab MetabolicMetabolicolic activation activation of of profosfamide profosfamide b bybyy the the the 4 4 4-methylene-group4---methylenemethylene---groupgroup hydroxylation hydroxylation.hydroxylation.. .
OO OO SS HHSS OO---NNaa++ MMeessnnaa
Figure 33. Structure of mesna. FigureFigure 33. 33. Structure Structure of of mesna mesna.. .
2.7.2.2.7.2. AArylrylryl---DialkylDialkyl---TriazinesTriazines AnotheAnotherrr classclassclass ofofof anticanceranticanceranticancer prodrugsprodrugsprodrugs thatthatthat areare activatedactivated byby alky alkylll---groupgroup metabolic metabolic hydroxylat hydroxylationionion isisis the the the arylaryl---dialkyldialkyl---trtrtriiiazinesazines [98,99[98,99[98,99].].]. TheThe antitumor antitumor 11---arylaryl---3,33,3---dimethyldimethyltriazinestriazinestriazines have have have the the the general general general structurestructurestructure shown shown shown in in in Figure Figure Figure 3 3 344... The The The prototype prototype prototype of of of this this this class class class of of of drugs drugs drugs is is is 5 5 5---(3,3(3,3(3,3---DimethylDimethyl---11---
Molecules 2020, 25, 1937 18 of 29
2.7.2. Aryl-Dialkyl-Triazines Another class of anticancer prodrugs that are activated by alkyl-group metabolic hydroxylation is theMolecules aryl-dialkyl-triazines 2020, 25, x FOR PEER [ 98REVIEW,99]. The antitumor 1-aryl-3,3-dimethyltriazines have the general structure18 of 29 shown in Figure 34. The prototype of this class of drugs is 5-(3,3-Dimethyl-1-triazeno)imidazole- 4-carboxamidetriazeno)imidazole (DTIC)-4-carboxamide (Figure 34), (DTIC) used in (Figure the treatment 34), used of in malignantthe treatment melanoma. of malignant The melanoma. metabolic activationThe metabolic of the activation aryl-dialkyl-triazines of the aryl-dialkyl is illustrated-triazines in is Figure illustrated 34. in Figure 34.
3 CONH N 2 CH 4 3 2 Ar N N N CH3 1 N 5 N N N 1 2 3 CH3 H CH3 Aryl-dimethyltriazine (I) 5-(3',3'-Dimethyl-1'-triazeno)imidazoe-4-carboxamide
(1) Alpha-hydroxylation of a methyl group
CH CH OH 3 (O) in the liver 2 Ar N N N Ar N N N CH3 CH3 (I) Alpha-hydroxyalkyltriazine (II) (2) Loss of the hydroxymethyl group from (II) as acetone and tautomerization of the resulting monomethyltriane to 3-aryl-1-methyltriazine, the DNA alkylating agent
CH OH H Ar N N N CH 2 Tautomerization 3 Ar N N N Ar N N N H 3-Aryl-1-methyltriazine CH3 CH3 (II) Monometyltriazine DNA-alkylating + H O Formadehyde H FigureFigure 34.34. Aryl-dialkyl-triazinesAryl-dialkyl-triazines and their metabolic activation.activation. 3. Further Interpretations 3. Further Interpretations When studying the effect of drug molecules’ metabolic hydroxy and carboxy functionalization When studying the effect of drug molecules’ metabolic hydroxy and carboxy functionalization of alkyl groups on metabolite pharmacologic activity, several factors should first be considered. of alkyl groups on metabolite pharmacologic activity, several factors should first be considered. These These factors include: factors include: (a) the extent of formation of the hydroxy and carboxy metabolites (a) the extent of formation of the hydroxy and carboxy metabolites (b)(b) the hydrophobicity of the parent drug and hydrophilicity ofof thethe metabolitesmetabolites (c)(c) the drug’s mechanism of action (d)(d) the favoredfavored site site of of metabolic metabolic hydroxylation hydroxylation in drugin drug molecules molecules containing containing more more than onethan alkyl one group alkyl (e) groupthe molecular size increase and steric effect resulting from the replacement of the small hydrogen (e) theatom molecular in the alkyl size groupincrease in and the steric drug effec moleculet resulting by the from larger the andreplacement bulkier hydroxylof the small or hydrogen carboxyl atomgroup in in the the alkyl metabolite group molecule in the drug molecule by the larger and bulkier hydroxyl or carboxyl (f) groupthe creation in the of metabolite new metabolite-receptor molecule binding mechanisms, e.g., hydrogen bonding, ion-pairing, (f) theand creation ion-dipole, of in new contrast metabolite to van-receptor der Waals binding binding mechanisms, of the alkyl groups e.g., hydrogen bonding, ion- pairing, and ion-dipole, in contrast to van der Waals binding of the alkyl groups Generally, the extent of the metabolic oxidation of carbon atoms in drug molecules’ alkyl chains dependsGenerally, in part the on extent the class of the of the metabolic carbon oxidation atom, which of carbon in turn atoms dictates in drug the stability molecules’ of the alkyl resulting chains freedepends radicals: in part benzylic, on the allylicclass of> thetertiary carbon> secondaryatom, which> inprimary turn di>ctatesmethyl. the stability On the otherof the hand, resulting the hydrophilicityfree radicals: benzylic of an alcoholic, allylic hydroxyl> tertiary group > secondary is determined > primary by the> methyl. strength On of the the other intermolecular hand, the hydrogenhydrophilicity bonds of it an forms. alcoholic Due to hydroxyl steric eff ects,group the is strength determined of hydrogen by the strength bonding inof thethe diintermolecularfferent classes ofhydrogen alcohols bonds follows it the for sequencems. Due primaryto steric >effects,secondary the strength> tertiary of [100 hydrogen]. The order bonding of the in hydrophilicity the different ofclasses primary, of alcohols secondary, follows and tertiary the sequence alcohols primary follows the > secondary same sequence. > tertiary [100]. The order of the hydrophilicityFrom the aliphatic of primary, hydroxy secondary and carboxy, and tertiary metabolites alcohols of the follows cases surveyed the same in sequen this review,ce. we observe threeFrom effects the on aliphatic the pharmacologic hydroxy and activity carboxy of metabolites the metabolites of the relevant cases surveyed to their parent in this drugs:review, loss, we attenuation,observe three or effects retention. on the pharmacologic activity of the metabolites relevant to their parent drugs: loss, attenuation, or retention.
3.1. NSAIDS Loss of pharmacologic activity has been observed for ibuprofen upon metabolic hydroxylation of the isobutyl group at C1, C2, and C3 (Figure 3). In analogy with the O-demethylation of the methoxy-group-containing NSAIDS discussed in the first part of this review series [12], both
Molecules 2020, 25, 1937 19 of 29
3.1. NSAIDS Loss of pharmacologic activity has been observed for ibuprofen upon metabolic hydroxylation of the isobutyl group at C1, C2, and C3 (Figure3). In analogy with the O-demethylation of the methoxy-group-containing NSAIDS discussed in the first part of this review series [12], both pharmacodynamic and pharmacokinetic effects may account for the ibuprofen isobutyl-hydroxy metabolites’ loss of pharmacologic activity. The SAR of ibuprofen dictates that the branched isobutyl moiety is essential for optimum COX-inhibitory effect; in this context, n-butyl substitution has led to significant loss of activity [101]. This finding should imply that each of the methyl groups in the isobutyl moiety occupies a small hydrophobic pocket in COX, enabling a pharmacophoric effect that is essential for optimum activity. The hydroxy and carboxy groups in metabolite III and metabolite IV, respectively (Figure3), are detrimental to the hydrophobic binding of the isobutyl group, and accordingly, they precipitate a loss of COX-inhibiting activity [102]. Further, by replacing a hydrogen atom in the isobutyl group in ibuprofen, the bulkier hydroxyl or carboxyl groups in the metabolites will impart molecular-size increase and steric effects—factors that are detrimental to optimum binding between isobutyl group and COX [102]. In addition, being hydrophilic, the hydroxyl or carboxyl group will increase the water solubility of the metabolites, hence leading to their elimination and termination of their action. Furthermore, glucuronide conjugation of the hydroxyl and carboxyl groups will considerably enhance the prospects of metabolite elimination and activity termination through substantially increasing aqueous solubility.
3.2. Sulfonylurea Oral Antidiabetics For the sake of discussing the effect of metabolic oxidation of alkyl and aliphatic cyclic groups in the sulfonylurea antidiabetics, we dissect the general structure of these agents, as depicted in Figure5. To reiterate, in the first-generation sulfonylureas (Section 2.2), R1 (Figure7) is a small lipophilic group, such as methyl or chloro, while R2 is an alkyl or aliphatic cyclic group. According to Foye (2020) [26], the R1 groups do little to increase the binding efficiency of the pharmacophore to the ATP-sensitive + K channel. As such, R1 groups may be playing weak auxiliary pharmacophoric and/or auxophoric roles. On the other hand, the R2 groups in both first- and second-generation sulfonylurea antidiabetics have the auxophoric role of optimizing the pKa of the sulfonylurea group to ~5. At this pKa value, a sulfonylurea anion is formed that is essential for interaction with the pancreatic β-cell subtypes (SUR1, SURA1, and SUR2A) through ion-ion and ion-dipole bindings [103]. Generally, metabolic change at auxiliary pharmacophores or auxophores is associated with retention of pharmacologic activity [12]. However, a discrepancy is observed for some members of the first-generation sulfonylurea antidiabetics in this respect. For instance, while the aliphatic-ring hydroxy metabolite of tolazamide (Figure 12) is active with a prolonged duration of action, the counterpart metabolite of acetohexamide (Figure8) is inactive. The lipophilic methyl group at R1 in the general structure of sulfonylureas (Figure5) is metabolized by oxidation, via hydroxymethyl formation, to the carboxyl group with loss of activity in both tolbutamide and tolazamide (Figures7 and9, respectively). Generally, the loss of activity caused by metabolically formed carboxyl groups can be explained by two effects. Firstly, the carboxyl group is almost fully ionized at the physiologic pH of 7.4. Secondly, the carboxyl group is, in most cases, glucuronide conjugated in phase II. These two effects will result in a substantial increase of water solubility and elimination of the metabolite with the consequent loss of activity due to reduced effective concentration of the metabolite at the receptor. It is noteworthy that the metabolic functionalization of the lipophilic benzylic methyl group to the carboxyl group in tolbutamide (Figure7), with the consequent enhanced elimination and loss of activity, has led to the development of chlorpropamide (Figure9). By employing bioisosterism, medicinal chemists replaced the benzylic methyl group in tolbutamide with a chloro group, which is not prone to metabolism, to obtain chlorpropamide. Due to this manipulation of metabolic stability, chlorpropamide can be used at a lower dose and frequency than tolbutamide [104]. Molecules 2020, 25, 1937 20 of 29
In the second-generation sulfonylurea antidiabetics, the small lipophilic groups of the first generation at R1 (Figure5) have been replaced by the larger p-(β-arylcarboxyamidoethyl) group, such as in glimepiride (Figure 14), in order to attain strong binding affinity to the ATP-sensitive K+ channel [26]. Metabolism of this group is not within the scope of this review.
3.3. Barbiturates The metabolic oxidative hydroxylation of alkyl chains in barbiturates has resulted in variable levels of activity subject to the class of the resulting alcohol. In pentobarbital (Figure 17), the primary and secondary alcohols, respectively resulting from ω and ω-1 oxidation, are sufficiently hydrophilic to jeopardize the hydrophobicity requirement for blood-brain barrier crossing [105]. In addition to hydrophilicity, the factors of increased steric effect, molecular size, and surface area may come into play to hinder the hydroxy metabolite from fitting in the receptor, thus leading to either attenuation or loss of activity as governed by the extent of each factor. On the other hand, in amobarbital (Figure 16), metabolic oxidation occurs mainly at the ω-1 tertiary carbon, resulting in a tertiary alcohol, 30-hydroxyamobarbital. Despite being less active, 30-hydroxyamobarbital has been reported to be responsible for the sedative-hypnotic activity of amobarbital [43]. With reduced hydrogen bonding ability, and the consequent diminishment of hydrophilicity, due to steric effects in tertiary alcohols, 30-hydroxyamobarbital is expected to cross the blood-brain barrier in sufficient concentration to produce sedative-hypnotic effects. The loss of activity of the carboxy metabolites of barbiturates may be explained similarly to the NSAIDS-carboxy metabolites (Section 3.1).
3.4. Accounting for the Activity of the H1-Antihistamines’ Carboxy Metabolites: Hydroxyzine, Terfenadine, and Ebastine Methyl groups that are bonded to aromatic or cycloalkyl rings, or terminal in alkyl chains (i.e., ω methyls) in drug molecules are usually oxidized to inactive carboxy metabolites through the formation of mostly active hydroxymethyl intermediates. The loss of pharmacologic activity indicates that the methyl groups in such cases play pharmacophoric roles, at least of an auxiliary nature. However, when the methyl or hydroxymethyl group is distant from a predetermined pharmacophore, the situation is different: metabolic oxidation of either group to the carboxyl group does not cause loss of activity of the resulting metabolite. This has been the case with the three H1-antihistamines hydroxyzine, terfenadine, and ebastine, which are respectively metabolized to equiactive cetirizine (Figure 24), fexofenadine (Figure 22), and carebastine (Figure 23). Hydroxyzine is a first generation H1-antihistamine. With a log P value of 3.5 [106], it is hydrophobic enough to cross the blood-brain barrier, interact with cholinergic, serotonergic, and adrenergic receptors and cause sedation [107]. On the other hand, cetirizine, the carboxy-metabolite drug of hydroxyzine, has a log P value of 1.5 [108] and exists as zwitterion at physiologic pH of 7.4. Due to these properties, cetirizine does not cross the blood-brain barrier and does not accordingly cause sedation. As shown in Figure 24, in both hydroxyzine and cetirizine, the metabolically exchanged groups are distant from the pharmacophore, and accordingly, the two drugs are therapeutically equiactive as H1-antihistamines. The ethoxyethanol group in hydroxyzine and the ethoxyacetic acid group in cetirizine each play an auxophoric role. A similar situation can be observed for the terfenadine/fexofenadine H1-antihistamine pair (Figure 23). However, here, the carboxyl group in fexofenadine plays a pharmacodynamic rather that a pharmacokinetic role. Terfenadine causes heart arrhythmias by blocking the hERG channel K+ current [109]. On the other hand, the ionized carboxylate group (COO−) in fexofenadine reduces this blockage by over three orders of magnitude, thus rendering this drug almost free of the cardiotoxic effect [110]. The inference that can be made from the two H1-antihistamine pairs presented above is that when metabolic changes occur at groups distant from the primary pharmacophores (i.e., at auxophoric groups), the original pharmacologic activity will not be affected. Further, beneficial pharmacokinetic Molecules 2020, 25, 1937 21 of 29 and/or pharmacodynamic modifications may result in the metabolites warranting their development into fully-fledged drugs. An extended definition of pharmacophores is given in Section 3.6.7.
3.5. Aspirin Is an NSAID of Its Own Disposition In salicin (Figure 27), the acetalic group is metabolically converted to a hydroxyl group in a reaction reminiscent of O-dealkylation, while the hydroxymethyl group is oxidized to the carboxyl group to give salicylic acid. The phenolic hydroxyl group in salicylic acid was suspected to be the cause of stomach irritation and bleeding, and it was hence esterified by acetic anhydride to give aspirin. However, later, it was proven [111–113] that the gastrointestinal adverse effects of aspirin were associated with the inhibition of COX1 and accordingly the inhibition of PGE1 formation, i.e., synthesis of the prostaglandin involved in the protection of gastric mucosa against acid attack. Sometime then elapsed before the mechanism of the anti-inflammatory activity of aspirin was understood to be caused by acetylation of the serine moiety in COX [114]. That being the case, the benzene ring and the carboxyl group in aspirin are likely playing auxiliary pharmacophoric roles by properly anchoring the aspirin molecule in the COX-active cavity, thus facilitating the transfer of the acetyl group to the serine moiety.
3.6. Subtexts Arising from Hydroxy and Carboxy Metabolic Functionalization of Alkyl Moieties in Drug Molecules The aim of this section is to provide focused information on some general and specific issues that have been extracted from the individual cases of alkyl-moiety metabolic hydroxy and carboxy functionalization. The information presented and discussed includes definitions, significance, implications, and/or applications of selected topics, which include:
3.6.1.Metabolism of methyl groups in drug molecules 3.6.2.Metabolic hydroxylation of alicycles and aliphatic heterocycles in drug molecules 3.6.3.Inferences from hydroxymethyl group in drug metabolites regarding origin and significance 3.6.4.Development of metabolite drugs and prodrugs from metabolites equiactive with parent drugs 3.6.5.Pharmacologic activity of carboxy metabolites 3.6.6.Significance of the carboxy metabolite of ∆9-tetrahydrocannabinol 3.6.7.Primary and auxiliary pharmacophoric properties
3.6.1. Metabolism of Methyl Groups in Drug Molecules Methyl groups assume their importance in drug molecules due to their small size, higher steric effect with respect to the hydrogen atom, hydrophobicity, isosterism with a number of groups, and historical inclusion in drug molecules. They are found in drug molecules at ω-carbons in both straight- and branched-chain alkyls, as substituents in aromatic (benzene) rings and alicycles, and as substituents in secondary and tertiary amino moieties. In branched-chain alkyls, methyl groups are found as isopropyl, isobutyl, or tert-butyl moieties. In all of these forms, the methyl group is metabolically oxidized by CYP450 enzymes to the hydroxymethyl group. The sequential oxidation of the latter group to the carboxylic acid follows in most cases via primary alcohol formation. When there is more than one equivalent methyl group in a drug molecule, only one group will be metabolically oxidized.
3.6.2. Metabolic Hydroxylation of Alicycles and Aliphatic Heterocycles in Drug Molecules Six-membered alicycle (cyclohexyl) and heterocycle (piperidinyl) groups are often encountered in drug molecules of various pharmacologic classes. For the most part, rings are stereoselectively metabolized by hydroxylation at the positions 3 and 4, which are less sterically hindered, compared to other positions (in the ring), to form cis and trans isomers. Pharmacologic action may also be a function of stereoselective metabolism. For instance, the oral antidiabetic acetohexamide is mainly metabolized to trans-40-hydroxyacetohexamide, which is inactive. The cyclohexyl ring in glibenclamide is metabolically oxidized to 3-cis and 4-trans-hydroxy metabolites with a substantial attenuation of Molecules 2020, 25, 1937 22 of 29 antidiabetic activity. A similar effect has been observed for tolazamide, in which the azepane ring is metabolically hydroxylated at position 4 (Figure 11) with a substantial loss of activity. An interesting case of metabolic hydroxylation of alicycles and aliphatic heterocycles is given Moleculesby the psychotropic2020, 25, x FOR PEER drug REVIEW phencyclidine, which contains both cyclohexyl and piperidinyl groups.22 of 29 Phencyclidine is mainly metabolized by hydroxylation at position 4 of the cyclohexyl ring to the activeactive cis-- and transtrans-4-phenyl-4-(1-piperidinyl)cyclohexanol-4-phenyl-4-(1-piperidinyl)cyclohexanol (Figure 35 35)[) [111515].]. In In addition, addition, the the piperidipiperidinylnyl ring ring in inphencyclidine phencyclidine is metabolically is metabolically hydroxylated hydroxylated to a minor to a extent minor at extent position at 4 position to give 44-phenyl to give-4 4-phenyl-4-(1-coclohexyl)piperidinyl-(1-coclohexyl)piperidinyl alcohol [116 alcohol]. The pharmacologic [116]. The pharmacologic activity of the activity piperidinyl of the- hydroxypiperidinyl-hydroxy metabolite of metabolite phencyclidine of phencyclidine has not been has reported. not been A t reported.entative inference A tentative can beinference made heedingcan be made the phencyclidine heeding the phencyclidine metabolic hydroxylation metabolic hydroxylation example: when example: an alicycle when an and alicycle aliphatic and heterocyclealiphatic heterocycle are parts are of parts the same of the molecule, same molecule, metabolic metabolic hydroxylation hydroxylation favors favors the alicycle the alicycle over over the heterocyclethe heterocycle..
OH
OH CYP3A4 + R R R Phencyclidine trans-isomer cis-isomer N 4-Phenyl-4-(1piperidinyl)cyclohexanol
4-Pheny-4-(cyclohexyl)piperidinyl alcohol
N OH FigureFigure 3 35.5. MetabolicMetabolic pathways pathways of of phencyclidine phencyclidine.. 3.6.3. Inferences from Hydroxymethyl Metabolites 3.6.3. Inferences from Hydroxymethyl Metabolites Hydroxymethyl groups (-CH2OH), either intrinsic to drug molecules or metabolically formed, play Hydroxymethyl groups (-CH2OH), either intrinsic to drug molecules or metabolically formed, pharmacophoric and/or auxophoric roles. Here, we highlight the significance of the hydroxymethyl play pharmacophoric and/or auxophoric roles. Here, we highlight the significance of the group as derived from the relevant cases in Section2. hydroxymethyl group as derived from the relevant cases in Section 2. Hydroxymethyl groups may be intrinsic to drug molecules, or they may result from the metabolic Hydroxymethyl groups may be intrinsic to drug molecules, or they may result from the oxidation of methyl groups bonded to aromatic or alicyclic rings or terminal methyl groups in alkyl metabolic oxidation of methyl groups bonded to aromatic or alicyclic rings or terminal methyl groups chains—i.e., ω carbons. Intrinsic or metabolically formed hydroxymethyl groups are almost invariably in alkyl chains—i.e., ω carbons. Intrinsic or metabolically formed hydroxymethyl groups are almost metabolically oxidized to carboxyl groups. invariably metabolically oxidized to carboxyl groups. The hydroxymethyl metabolites are almost invariably equiactive with the parent drugs, whereas The hydroxymethyl metabolites are almost invariably equiactive with the parent drugs, whereas the carboxy metabolites (resulting from the sequential oxidation of the hydroxymethyl metabolites) are the carboxy metabolites (resulting from the sequential oxidation of the hydroxymethyl metabolites) mostly inactive with only a few exceptions being equiactive with the parent drugs. These exceptional are mostly inactive with only a few exceptions being equiactive with the parent drugs. These cases are those in which the hydroxymethyl groups are distant from the primary pharmacophore. exceptional cases are those in which the hydroxymethyl groups are distant from the primary The fact that hydroxymethyl metabolites invariably retain the pharmacologic activity due to the pharmacophore. parent drug probably reflects the auxiliary pharmacophoric status of the methyl group from which The fact that hydroxymethyl metabolites invariably retain the pharmacologic activity due to the they have resulted. parent drug probably reflects the auxiliary pharmacophoric status of the methyl group from which Of the hydroxymethyl metabolites that are equiactive with their parent drugs, only that of they have resulted. tolterodine has been developed into a prodrug, which carries the name of fesoterodine (Figure 20). Of the hydroxymethyl metabolites that are equiactive with their parent drugs, only that of tolterodine3.6.4. Development has been ofdeveloped Metabolite into Drugs a prodrug and Prodrugs, which carries from Parent-Drug the name of Equiactivefesoterodine Metabolites (Figure 20).
3.6.4. TheDevelopment metabolite of drugs Metabolite presented Drugs in Sectionand Prodrug1 includes from the Parent H1-antihistamines-Drug Equiactive cetirizine Metabolites (Figure 24) and fexofenadine (Figure 22), the carboxy metabolites of hydroxyzine and terfenadine, respectively. The metabolite drugs presented in Section 1 include the H1-antihistamines cetirizine (Figure 24) Both drugs are more hydrophilic than their respective parent drugs and are capable of existing as and fexofenadine (Figure 22), the carboxy metabolites of hydroxyzine and terfenadine, respectively. zwitterions at physiologic pH. Due to these properties, the two drugs do not cross the blood-brain Both drugs are more hydrophilic than their respective parent drugs and are capable of existing as barrier, and accordingly, they do not cause sedation. In addition, the carboxyl group in fexofenadine zwitterions at physiologic pH. Due to these properties, the two drugs do not cross the blood-brain seems to offer an ionic binding site that is responsible for the removal of cardiotoxic adverse effects from barrier, and accordingly, they do not cause sedation. In addition, the carboxyl group in fexofenadine seems to offer an ionic binding site that is responsible for the removal of cardiotoxic adverse effects from the parent drug terfenadine. The advantages of both cetirizine and fexofenadine that warranted their development into metabolite drugs may be described as intrinsic. However, cases are known in which these advantages are artificially produced, such as in metabolite prodrugs. In such cases, the metabolite is equiactive with the parent drug, but due to high hydrophilicity, it suffers the disadvantages of low bioavailability and short duration of action. Chemists have responded to this
Molecules 2020, 25, 1937 23 of 29 the parent drug terfenadine. The advantages of both cetirizine and fexofenadine that warranted their development into metabolite drugs may be described as intrinsic. However, cases are known in which these advantages are artificially produced, such as in metabolite prodrugs. In such cases, the metabolite is equiactive with the parent drug, but due to high hydrophilicity, it suffers the disadvantages of low bioavailability and short duration of action. Chemists have responded to this situation by producing ester prodrugs. The two metabolite prodrugs presented in Section2 are the antipsychotic paliperidone palmitate (Section 2.4.2, Figure 17) and the antimuscarinic fesoterodine (Section 2.4.5, Figure 21). The development of ester prodrugs of hydroxy metabolites equiactive with their parent drugs to attain improved pharmacokinetic properties may be extended to other cases if sufficiently warranted.
3.6.5. Pharmacologic Activity of Carboxy Metabolites In most of the surveyed drugs in Section2, where terminal methyls in alkyl chains ( ω-carbons), benzylic methyls, and methyls directly bonded to alicycles are metabolically oxidized to the carboxy group, a loss of pharmacologic activity due to the parent drug has been observed. However, two cases, terfenadine and ebastine, are unique in that the oxidation of the benzylic methyl group has resulted in retention of pharmacologic activity. In these two particular cases, the metabolic oxidation of the methyl group to the carboxyl group has taken place at positions distant from the primary pharmacophores: terfenadine and ebastine (Figures 20 and 21, respectively). Of all the metabolically generated polar functional groups in drug molecules, the carboxyl group stands alone in that it is almost completely ionized at the physiologic pH of 7.4. If such metabolic change occurs at a pharmacophoric site, the new state of ion-pairing interactions replacing the van der Waals interaction of the methyl group will tend to change the pharmacodynamics of the parent drug, leading to a loss of activity. On the other hand, the ionized carboxyl group introduces a pharmacokinetic dimension—which substantially enhances the polarity, water solubility, and elimination of the metabolite as per se or as the glucuronide conjugate, thus causing a significant reduction of the metabolite’s effective concentration at the receptor. It is noteworthy that when a carboxyl group is involved in zwitterion formation with an aliphatic amino group, such as in fexofenadine, carebastine, and cetirizine, it (the carboxy group) will not be subject to glucuronide conjugation. In fact, glucuronide conjugation has not been reported as a metabolic route for any of the three aforementioned drugs.
3.6.6. Significance of the Carboxy Metabolite of ∆9-Tetrahydrocannabinol ∆9-Tetrahydrocannabinol (Figure 20) is the major psychoactive constituent of Cannabis sativa. The use of Cannabis products, hashish and marijuana, is illegal in many countries and is punishable by law. The detection of cannabis-product use is based on urinalysis of the constituent metabolites. For this purpose, presumptive immunoassays have been developed based on the carboxy metabolite of ∆9-tetrahydrocannabinol, i.e., carboxy-∆9-tetrahydrocannabinol (Figure 21). Confirmation tests of the presence of this metabolite are carried out by chromatography-mass spectrometry methods such as GC-MS after trimethylsilyl derivatization or LC-MS [117,118].
3.6.7. Primary and Auxiliary Pharmacophores In the first part of this review series [12], we classified the pharmacophore as primary and auxiliary (secondary or logistic) based on the “message/address” concept suggested by Dr. Portoghese [119]. The case of fexofenadine development as a metabolite drug of terfenadine (Figure 24) due to the cardiotoxicity of the latter has prompted us to extend the definition of an auxiliary pharmacophore. An auxiliary pharmacophore is a group that may play one of two roles: (a) properly anchoring the primary pharmacophore in the active site of the receptor or enzyme, or (b) interacting with a site other than the primary site (i.e., an auxiliary site) to produce or override an adverse effect or to account for an off-label use of the drug. Hence, the cardiotoxic effect of terfenadine may be explained by the interaction of the three benzylic methyl groups with an auxiliary receptor via van der Waals binding. On the other hand, in fexofenadine, one of the benzylic methyl groups (in terfenadine) has been Molecules 2020, 25, 1937 24 of 29 metabolically oxidized to a carboxyl group, which interacts with the auxiliary site via ionic binding. Due to its higher strength, ionic binding strongly predominates over van der Waals binding and thus dictates, in part, the nature of the pharmacologic activity of drugs in which it occurs.
4. Conclusions The occurrence and extent of alkyl moiety hydroxy functionalization in drug molecules is predictable based on the feasibility of intermediate free radicals’ formation and stability. On the other hand, the pharmacologic activities of the alkyl moieties-hydroxy and carboxy metabolites may be predicted based on analogy with the reviewed cases. All hydroxymethyl metabolites are pharmacologically equiactive with their parent drugs while most carboxy metabolites are inactive. The development of metabolite ester prodrugs has an extendable potential when the equiactive hydroxy metabolite is characterized by poor bioavailability and/or short duration of action. The pharmacologic activities of the hydroxy and carboxy metabolites resulting respectively from alkyl or hydroxymethyl moiety functionalization are explicable on pharmacodynamic and/or pharmacokinetic grounds. In some cases, metabolic hydroxy and carboxy functionalization of alkyl or hydroxymethyl moieties has enabled distinctions to be made between primary pharmacophores, auxiliary pharmacophores, and auxophores.
Author Contributions: The authors have contributed equally to the preparation of this review. All authors have read and agreed to the published version of the manuscript. Funding: The work was self-funded by the authors. Conflicts of Interest: The authors declare no conflict of interest.
References
1. Zavod, R.M.; Knittel, J.J. Drug design and relationship of functional groups to pharmacologic activity. In Foye’s Principles of Medicinal Chemistry, 7th ed.; Lemke, T., Williams, D.A., Roche, V.F., Zito, S.W., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2013; p. 51. ISBN 978-1-60913-345-0. 2. Wang, J.; Wu, Y.; Ma, C.; Fiorin, G.; Wang, J.; Pinto, L.H.; Lamb, R.A.; Klein, M.L.; William, F.; DeGrado, W.F. Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus. Proc. Natl. Acad. Sci. USA 2013, 110, 1315–1320. [CrossRef][PubMed] 3. Iversen, L. Handbook of Psychopharmacology, Affective Disorders: Drug Disorders in Animal and Man; Iversen, L.L., Iversen, S., Eds.; Prenum Publishing Corporation: New York, NY, USA, 2013; Volume 14, p. 96. ISBN 978-1-4613-4045-1. 4. De Montellano, P.R.O. Hydrocarbon hydroxylation by cytochrome p450 enzymes. Chem. Rev. 2010, 110, 932. [CrossRef][PubMed] 5. Mehta, S. Phase I Metabolism-Oxidative Reactions-Oxidation of Aliphatic and Alicyclic Compounds. Medicinal Chemistry Notes, Pharmacology, Pharmaxchange. 7 September 2014. Available online: https://pharmaxchange.info/2014/09/phase-i-metabolism-oxidative-reactions-oxidation-of-aliphatic- and-alicyclic-compounds/ (accessed on 28 February 2019). 6. Reilly, C.A.; Yost, G.S. Structural and enzymatic parameters that determine alkyl dehydrogenation/hydroxylation of capsaicinoids by cytochrome p450 enzymes. Drug Metab. Dispos. 2005, 33, 530–536. [CrossRef][PubMed] 7. Williams, D.A. Drug metabolism. In Foye’s Principles of Medicinal Chemistry, 7th ed.; Lemke, T., Williams, D.A., Roche, V.F., Zito, S.W., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2013; p. 126. ISBN 978-1-60913-345-0. 8. Approaches of Classical Medicinal Chemistry. Available online: http://www.chem.uzh.ch/zerbe/MedChem/ MedChem4_MedChem.pdf (accessed on 25 March 2020). 9. Guengeric, F.P. Mechanisms of cytochrome P450 substrate oxidation: MiniReview. J. Biochem. Mol. Toxicol. 2007, 21, 163–168. [CrossRef] 10. Obrien, P.J. Multiple mechanisms of activation of aromatic amine carcinogens. In Free Radicals in Biology; Pryor, N.A., Ed.; Academic Press Inc.: London, UK, 1984; Volume 6, p. 294. ISBN 0-12-566506-7. Molecules 2020, 25, 1937 25 of 29
11. Stability of Free Radicals. Available online: http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch04/ch4-4- 1.html (accessed on 18 March 2020). 12. El-Haj, B.M.; Ahmed, S.B.M.; Garawi, M.A.; Ali, H.S. Linking aromatic hydroxy metabolic functionalization of drug molecules to structure and pharmacologic activity. Molecules 2018, 23, 2119. [CrossRef] 13. Bushra, R.; Aslam, N. An overview of clinical pharmacology of ibuprofen. Oman Med. J. 2010, 25, 155–166. [CrossRef] 14. Evans, A.M. Comparative pharmacology of S-(+)-Ibuprofen and (RS)-Ibuprofen. Clin. Rheumatol. 2001, 20, 9–14. [CrossRef] 15. Stock, K.P.; Geisslinger, G.; Loew, D.; Beck, W.S.; Bach, G.L.; Brune, K. S-Ibuprofen versus ibuprofen-racemate. Rheumatol. Internat. 1991, 11, 199–202. [CrossRef] 16. Davies, N.M. Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin. Pharmacokinet. 1998, 34, 101–154. [CrossRef] 17. Geisslinger, G.; Schuster, O.; Stock, K.P.; Loew, D.; Bach, G.L.; Brune, K. Pharmacokinetics of s dextro and r levo ibuprofen in volunteers and first clinical experience of s dextro ibuprofen in rheumatoid arthritis. Eur. J. Clin. Pharmacol. 1990, 38, 493–498. [CrossRef] 18. Rudy, A.C.; Knight, P.M.; Brater, D.C.; Hall, S.D. Stereoselective metabolism of ibuprofen in humans: Administration of R-, S- and racemic ibuprofen. J. Pharmacol. Exp. Ther. 1991, 259, 1133–1139. [PubMed] 19. Mazaleuskaya, L.; Theken, K.N.; Gong, L.; Thorn, C.F.; FitzGerald, G.A.; Altman, R.B.; Klein, T.E. PharmGKB summary: Ibuprofen pathways. Pharmacogenet. Genomics 2015, 25, 96–106. [CrossRef][PubMed] 20. Kasprzyk-Horder, B. Pharmacologically active compounds in the environment and their chirality. Chem. Soc. Rev. 2010, 39, 4466–4503. [CrossRef][PubMed] 21. Kepp, D.R.; Sidelmann, U.G.; Tjørnelund, J.; Hansen, S.H. Simultaneous quantitative determination of the major phase I and II metabolites of ibuprofen in biological fluids by high-performance liquid chromatography on dynamically modified silica. J. Chromatogr. B Biomed. Sci. Appl. 1997, 696, 235–241. [CrossRef] 22. North, E.J. Drugs used to treat pain: peripherally acting agents. In Foye’s Principles of Medicinal Chemistry, 8th ed.; Roche, V.F., Zito, S.W., Lemke, T.L., Williams, D.A., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2020; p. 573. ISBN 978-1-4963-8502-4. 23. Mills, R.F.N.; Adams, S.S.; Dickinson, W.; Nicholson, J.S. The Metabolism of Ibuprofen. Xenobiotica 1973, 3, 589–598. [CrossRef] 24. Summer, D.D.; Dayton, P.G.; Cucinell, S.A.; Plostnieks, J. Metabolism of tolmetin in rat, monkey, and man. Drug Metab. Dispos. 1975, 3, 283–286. 25. Inactive Tolmetin metabolites. Available online: https://www.drugbank.ca/drugs/DB00500 (accessed on 21 March 2020). 26. Zito, S.W. Drugs used to treat diabetic disorders. In Foye’s Principles of Medicinal Chemistry, 8th ed.; Roche, V.F., Zito, S.W., Lemke, T.L., Williams, D.A., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2020; pp. 804–805. ISBN 978-1-4963-8502-4. 27. Kharbanda, C.; Alam, S.M. Evolution of sulfonylureas in the treatment of diabetes mellitus. Chem. Biol. Interface 2013, 3, 230–252. 28. Ashcroft, F.M. Mechanisms of the glycemic effects of sulfonylureas. Horm. Metab. Res. 1996, 28, 456–463. [CrossRef] 29. McMahon, R.E.; Marshall, F.J.; Culp, H.W. The nature of the metabolites of acetohexamide in the rat and in the human. J. Pharmacol. Exptl. Therap. 1965, 149, 272–279. 30. Galloway, J.A.; McMahon, R.E.; Culp, H.W.; Marshall, F.J.; Young, E.C. Metabolism, blood levels and rate of excretion of acetohexamide in human subjects. Diabetes 1967, 16, 118–127. [CrossRef] 31. Thomas, R.C.; Ikeda, G.J. The metabolic fate of tolbutamide in man and in the rat. J. Med. Chem. 1966, 9, 507–510. [CrossRef] 32. Tolbutamide. Available online: https://www.drugbank.ca/drugs/DB01124 (accessed on 21 March 2020). 33. Ashenhurst, J. Free radical Reactions. Available online: https://www.masterorganicchemistry.com/2013/08/ 02/3-factors-that-stabilize-free-radicals/ (accessed on 20 March 2020). 34. Skillman, S.G. Chlorpropamide metabolism. Am. J. Med. 1981, 71, 1050. [CrossRef] 35. Thomas, R.C.; Duchamp, D.J.; Judy, R.W.; Ikeda, G.J. Metabolic fate of tolazamide in man and in the rat. J. Med. Chem. 1978, 21, 725–732. [CrossRef][PubMed] 36. Glyburide. Available online: https://www.drugbank.ca/drugs/DB01016 (accessed on 21 March 2020). Molecules 2020, 25, 1937 26 of 29
37. Peart, G.F.; Boutagy, J.; Shenfield, G.M. The metabolism of glyburide in subjects of known debrisoquin phenotype. Clin. Pharmacol. Ther. 1989, 45, 277–284. [CrossRef] 38. Glimepiride. Available online: https://www.pharmgkb.org/chemical/PA449761/overview (accessed on 17 January 2020). 39. Glimepiride. Available online: https://www.drugbank.ca/drugs/DB00222 (accessed on 20 February 2019). 40. Wensing, G. Glipizide: An oral hypoglycemic drug. Am. J. Med. Sci. 1989, 298, 69–71. [CrossRef][PubMed] 41. Löscher, W.; Rogawski, M.A. How theories evolved concerning the mechanism of action of barbiturates. Epilepsia 2012, 53, 12–25. [CrossRef] 42. Kamm, J.J.; Van Loon, E.J. Amobarbital metabolism in man: A gas chromatographic method for the estimation of hydroxyamobarbital in human urine. Clin. Chem. 1966, 12, 789–796. [CrossRef] 43. Lowry, W.T.; Garriott, J.C. Controlled and non-controlled but commonly abused drugs. In Forensic Toxicology of Controlled Substances and Dangerous Drug; Plenum Press: New York, NY,USA, 1979; p. 68. ISBN 978-1-4684-3446-0. 44. Moniri, N.H. Drugs used to induce/support sedation and anesthesia. In Foye’s Principles of Medicinal Chemistry, 8th ed.; Roche, V.F., Zito, S.W., Lemke, T.L., Williams, D.A., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2020; p. 493. ISBN 978-1-4963-8502-4. 45. Moniri, N.H. Sedative hypnotics. In Foye’s Principles of Medicinal Chemistry, 7th ed.; Lemke, T., Williams, D.A., Roche, V.F., Zito, S.W., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2013; p. 491. ISBN 978-1-60913-345-0. 46. Valproic Acid Pathway, Pharmacodynamics. PHARMGKB. Available online: https://www.pharmgkb.org/ pathway/PA165959313 (accessed on 28 February 2019). 47. Loscher, W. Anticonvulsant activity of metabolites of valproic acid. Arch. Int. Pharmacody. Ther. 1981, 249, 158–163. 48. Bello-Ramirez, A.M.; Carreon, B.Y.; Nara-Ocampo, A.A. Do structural properties explain the anticonvulsant activity of valproate metabolites? A QSAR analysis. Epilepsia 2002, 43, 475–481. [CrossRef] 49. Canal, C.E.; Booth, R.G.; Williams, D.A. Drugs used to treat mental, behavioral and cognitive disorders. In Foye’s Principles of Medicinal Chemistry, 8th ed.; Roche, V.F., Zito, S.W., Lemke, T.L., Williams, D.A., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2020; p. 330. ISBN 978-1-4963-8502-4. 50. De Leon, J.; Wynn, G.; Sandson, N.B. The Pharmacokinetics of paliperidone versus risperidone. Psychosomatics 2010, 61, 80–88. [CrossRef] 51. Alamo, C.; Lopez-Mufioz, F. The pharmacological role and clinical applications of antipsychotics’ active metabolites: Paliperidone versus risperidone. Clin. Exptl. Pharmacol. 2013, 3, 117–128. 52. Yasui-Furukori, N.; Hidestrand, M.; Spina, E.; Facciolá, G.; Scordo, M.G.; Tybring, G. Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab. Dispos. 2001, 10, 1263–1268. 53. Sedky, K. Paliperidone palmitate: Once-monthly treatment option for schizophrenia. Curr. Psychiatry 2010, 9, 48–49. 54. Skarydova, L.; Tomanova, R.; Havlikova, L.; Stambergova, H.; Solich, P.; Wsol, V. Deeper insight into the reducing biotransformation of bupropion in the human liver. Drug Metab. Pharmacokinet. 2014, 29, 177–184. [CrossRef][PubMed] 55. Masters, A.R.; Gufford, B.T.; Lu Jessica, B.L.; Metzger, I.F.; Jones, D.R.; Desta, Z. Chiral plasma pharmacokinetics and urinary excretion of bupropion and metabolites in healthy volunteers. J. Pharmacol. Exp. Ther. 2016, 358, 230–238. [CrossRef] 56. Sharma, P.; Murthy, P.; Srinivas, M.M. Chemistry, metabolism, and toxicology of cannabis: Clinical implications. Iran J. Psychiatry 2012, 7, 140–156. 57. Mechoulam, R.C.; Hanus, L.O.; Pertwee, R.; Howlett, A.C. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat. Rev. Neurosci. 2014, 5, 757–764. [CrossRef] 58. Malhorta, B.; Gandelman, K.; Sachse, R.; Wood, N.; Michel, M.C. The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine. Curr. Med. Chem. 2009, 6, 4481–4489. 59. Simona, H.; Malhotra, B. The pharmacokinetic profile of fesoterodine: Similarities and differences to tolterodine. Swiss Med. Wkly. 2009, 139, 146–151. 60. Malhorta, B.; Guan, Z.; Wood, N.; Gandelman, K. Pharmacokinetic profile of fesoterodine. Int. J. Clin. Pharmacol. Ther. 2008, 45, 556–563. Molecules 2020, 25, 1937 27 of 29
61. Postlind, H.; Danielson, A.; Lindgren, A.; Andersson, S.H. Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab. Despos. 1998, 26, 289–293. 62. Fifer, E.K. Drugs used to treat allergic disorders. In Foye’s Principles of Medicinal Chemistry, 8th ed.; Roche, V.F., Zito, S.W., Lemke, T.L., Williams, D.A., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2020; pp. 1015–1016. ISBN 978-1-60913-345-01058-1059. 63. Delgado, L.F.; Pferferman, A.; Sole, D.; Naspitz, C.K. Evaluation of the potential cardiotoxicity of the antihistamines terfenadine, astemizole, loratadine, and cetirizine in atopic children. Ann. Allergy Asthma Immunol. 1998, 80, 333–337. [CrossRef] 64. Simons, H.; Simons, K.J. Histamine and H1-antihistamines: Celebrating a century of progress. J. Allergy Clin. Immunol. 2011, 128, 1139–1150. [CrossRef][PubMed] 65. Chen, C. Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine. Curr. Med. Chem. 2008, 21, 2173–2191. [CrossRef][PubMed] 66. Del Cuvillo, A.; Mullol, J.; Bartra, J.; Dávila, I.; Jáuregui, I.; Montoro, J.; Sastre, J.; Valero, A.L. Comparative pharmacology of the H1 antihistamines. J. Investig. Allergol. Clin. Immunol. 2006, 16, 3–12. 67. Khojasteh, S.C.; Wong, H.; Hop, C.E.C.A. Drug Metabolism and Pharmacokinetics Quick Guide; Springer: New York, NY, USA, 2011; p. 171. ISBN 978-1-4419-5628-6. 68. Hey, J.A.; del Prado, M.; Sherwood, J.; Kreutner, W.; Egan, R.W. Comparative analysis of the cardiotoxicity proclivities of second-generation antihistamines in an experimental model predictive of adverse clinical ECG effects. Arzneimittelforschung 1996, 46, 153–158. 69. Carebastine (LAS X 113). Available online: https://adisinsight.springer.com/drugs/800003600 (accessed on 15 March 2020). 70. Nelson, W.L. Antihistamines and related antiallergic and antiulcer agents. In Foye’s Principles of Medicinal Chemistry, 7th ed.; Lemke, T., Williams, D.A., Roche, V.F., Zito, S.W., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2013; p. 1052. ISBN 978-1-60913-345-0. 71. Nelson, W.I. Antihistamines and related antiallergic and antiulcer agents. In Foye’s Principles of Medicinal Chemistry, 7th ed.; Lemke, T., Williams, D.A., Roche, V.F., Zito, S.W., Eds.; Wolters Kluwer and Lippincort Williams and Wilkins: London, UK, 2013; p. 1060. ISBN 978-1-60913-345-0. 72. Curran, M.; Scott, I.J.; Perry, C.M. Cetirizine: A review of its use in allergic disorders. Drugs 2004, 64, 523–561. [CrossRef][PubMed] 73. Stone, E. Salilixalba: An account of the success of the bark of the willow in the cure of agues. Philos. Trans. R. Soc. Lond. 1763, 53, 195–200. 74. Mahdi, J.G. Medicinal potential of willow: A chemical perspective of aspirin discovery. J. Saudi. Chem. Soc. 2010, 14, 317–322. [CrossRef] 75. Lei, J.; Zhour, Y.; Xie, D.; Zhang, Y. Mechanistic insights into a classic wonder drug-aspirin. J. Am. Chem. Soc. 2015, 137, 70–73. [CrossRef][PubMed] 76. Patrono, C.; Baigent, C.; Hirsh, J. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008, 33, 199S–233S. [CrossRef][PubMed] 77. Patrono, D.G. Platelet activation and artherothrombosis. N. Engl. J. Med. 2007, 357, 2482–2494. 78. Coccheri, S. Antiplatelet drugs: Do we need more options? Drugs 2010, 70, 887–908. [CrossRef][PubMed] 79. Aspirin and Cancer Prevention: What the Research Really Shows. Available online: https://www. cancer.org/latest-news/aspirin-and-cancer-prevention-what-the-research-really-shows.html (accessed on 17 March 2020). 80. Aspirin to Reduce Cancer Risk. Available online: https://www.cancer.gov/about-cancer/causes-prevention/ research/aspirin-cancer-risk (accessed on 17 March 2020). 81. Harrold, M. Agents Affecting the renin-angiotensin pathway and calcium blockers. In Foye’s Principles of Medicinal Chemistry, 7th ed.; Lemke, T.L., Williams, D.A., Roche, V.F., Zito, S.W., Eds.; Wolters Kluwer and Lippincott Williams and Wilkins: London, UK, 2013; p. 763. ISBN 978-1-60913-345-0. 82. Stearns, R.A.; Chakravatry, P.K.; Chen, R.; Chin, S.H. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfaminly members. Drug Metab. Dispos. 1995, 23, 207–215. [PubMed] Molecules 2020, 25, 1937 28 of 29
83. Iwamura, A.; Fukami, T.; Nakaajima, M.; Yokoi, T. CYP2C9 mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay. Drug Metab. Dispos. 2011, 39, 838–846. [CrossRef] [PubMed] 84. Altahir, S.L. Phase I reactions Oxidative Reactions. Available online: https://slideplayer.com/slide/14180376/ (accessed on 19 February 2020). 85. Gante, K.M.F. Metabolic Changes of Drugs and Related Organic Compounds. Available online: https: //www.scribd.com/presentation/215273318/3-Metabolism (accessed on 19 February 2020). 86. Perucca, E.; Gatti, G.; Cipolla, G.; Spina, E.; Barel, S.; Soback, S.; Gips, M.; Bialer, M. Inhibition of diazepam metabolism by fluvoxamine: A pharmacokinetic study in normal volunteers. Clin. Pharmacol. Ther. 1994, 56, 471–476. [CrossRef] 87. Greenblatt, D.J.; Woo, E.; Allen, M.D.; Orsulak, P.J.; Shader, R.I. Rapid recovery from massive diazepam overdoses. J. Am. Med. Assoc. 1978, 420, 1872–1874. [CrossRef] 88. Benzodiazepine Pathway, Pharmacokinetics. Available online: https://www.pharmgkb.org/pathway/ PA165111375 (accessed on 21 March 2020). 89. Vree, T.B.; Baars, A.M.; Wuis, E.W. HPLC analysis and pharmacokinetics of the enantiomers of R,S-oxazepam and R,S-temazepam with their corresponding glucuronide conjugates in urine and plasma of man. Acta Neuropsychiatr. 1990, 2, 95–100. [CrossRef] 90. Vree, T.B.; Baars, A.M.; Wuis, E.W. Direct high-pressure liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their corresponding glucuronide conjugates. Pharm. Weekbl. 1991, 13, 83–90. [CrossRef] 91. Liu, J.; Stewart, J.T. Simultaneous separation of diazepam and its chiral and achiral metabolites by HPLC on a chiralcel OD-R column. J. Anal. Lett. 1997, 30, 1555–1566. [CrossRef] 92. Pham-Huy, C.; Villain-Pautet, G.; Hua, H.; Chikhi-Chorfi, N.; Galons, H.; Thevenin, M. Separation of oxazepam, lorazepam, and temazepam enantiomers by HPLC on a derivatized cyclodextrin-bonded phase: Application to the determination of oxazepam in plasma. J. Biochem. Biophys. Methods 2003, 54, 287–289. [CrossRef] 93. Greenblatt, D.J.; von Moltke, L.L.; Harmatz, J.S.; Ciraulo, D.A.; Shader, R.I. Alprazolam pharmacokinetics, metabolism, and plasma levels: Clinical implications. J. Clin. Psychiatry 1993, 54, 42–51. 94. Vredenburg, G.; den Braver-Sewradj, S.; van Vugt-Lussenburg, B.M.; Vermeulen, N.P.; Commandeur, J.N.; Vos, J.C. Activation of the anticancer drugs cyclophosphamide and ifosfamide by cytochrome P450 BM3 mutants. Toxicol. Lett. 2014, 232, 182–192. [CrossRef] 95. Wang, D.; Wang, H. Oxazaphosphorine bioactivation and detoxification: The role of xenobiotic receptors. Acta Pharm. Sin. 2012, 2, 107–127. [CrossRef][PubMed] 96. Shaw, I.C.; Graham, M.I. Mesna—A short review. Cancer Treat. Rev. 1987, 14, 67–86. [CrossRef] 97. Daly, J. Chapter 29: Enzymic oxidation at carbon: Hydroxylation of carbon α to a heteroatom. In Heubner, H. Handbook of Experimental Pharmacology; Eichler, O., Farah, A., Herken, H., Welch, A.D., Eds.; Springer: New York, NY, USA, 1971; Volume 28/2, p. 289. ISBN 978-3-642-65179-3. 98. Vaughan, K. Triazeines. In The Chemistry of Antitumor Agents; William, D.E.V., Ed.; Chapman and Hall: New York, NY, USA, 1990; p. 261. ISBN 978-94-101-6665-5. 99. Griffin, R.J. The medicinal chemistry of the azido group. In Progress in Medicinal Chemistry; Ellis, G.P., Luscombe, D.K., Eds.; Elsevier Science: Amsterdam, The Netherlands, 1994; Volume 31, pp. 121–232. ISBN 0-444-81807-3. 100. Chandra, A.K.; Sannigrahi, A.B. Hydrogen-bonding properties of alcohols. J. Phys. Chem. 1965, 69, 2494–2499. [CrossRef] 101. DeRuiter, J. Non-steroidal Anti-inflammatory Drugs (NSAIDS). Available online: www.auburn.edu/ ~{}deruija/nsaids_2002.pdf (accessed on 20 March 2020). 102. Harrold, M.W.; Zavod, R.M. Functional group characteristics and roles. In Basic Concepts in Medicinal Chemistry, 2nd ed.; ASHP; Bethesda: Rockville, MD, USA, 2018; pp. 33–78. ISBN 978-1-58528-266-1. 103. Meyer, M.; Chudziak, F.; Schwanstecher, C.; Schwanstecher, M.; Panten, U. Structural requirements of sulfonylureas and analogues for interaction with sulfonylurea receptor subtypes. Br. J. Pharmacol. 1999, 128, 27–31. [CrossRef] 104. Patani, G.A.; LaVoie, E.J. Bioisosterism: A rational approach in drug design. Chem. Rev. 1996, 96, 3147–3176. [CrossRef] Molecules 2020, 25, 1937 29 of 29
105. Pajouhesh, H.; George, R.; Lenz, D.R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2005, 2, 541–553. [CrossRef] 106. Audeef, A. Absorption and Drug Development: Solubility, Permeability and Charge State; John Wily and Sons, Inc.: Hoboken, NJ, USA, 2003; p. 62. ISBN 0-471-42365-1. 107. Levander, S.; Stahle-Backdahi, M.; Hagemark, O. Peripheral antihistamine and central sedative effects of single and continuous oral doses of cetirizine and hydroxyzine. Eur. J. Clin. Pharmacol. 1991, 41, 435–439. [CrossRef] 108. Pagliara, A.; Testa, B.; Carrupt, P.; Jolliet, P.; Morin, C.; Morin, D.; Urien, S.; Tillement, J.; Rihoux, J. Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic h1-receptor antagonist. J. Med. Chem. 1998, 41, 853–863. [CrossRef][PubMed] 109. Sanguinetti, M.C.; Tristani-Firouzi, M. HERG potassium channels and cardiac arrhythmia. Nature 2006, 440, 463–469. [CrossRef][PubMed] 110. Scherer, C.R.; Lerche, C.I.; Decher, N.; Dennis, A.T.; Maier, P.; Ficker, E.; Busch, A.E.; Wollnik, B.; Steinmeyer, K. The antihistamine fexofenadine does not affect IKr currents in a case report of drug-induced cardiac arrhythmia. Br. J. Pharmacol. 2002, 137, 892–900. [CrossRef][PubMed] 111. Russell, R.I. Non-steroidal anti-inflammatory drugs and gastrointestinal damage—Problems and solutions. Postgrad. Med. J. 2001, 77, 82–88. [CrossRef] 112. Radi, Z.A.; Khan, N.K. Effects of cyclooxygenase inhibition on the gastrointestinal tract. Exp. Toxicol. Pathol. 2006, 58, 163–173. [CrossRef] 113. Van Oijen, M.G.; Dieleman, J.P.; Laheij, R.J.; Sturkenboom, M.C.; Jansen, J.B.; Verheugt, F.W. Peptic ulcerations are related to systemic rather than local effects of low-dose aspirin. Clin. Gastroenterol. Hepatol. 2008, 6, 309–313. [CrossRef] 114. Vane, J.R.; Botting, R.M. The mechanism of action of aspirin. Thromb. Res. 2003, 10, 255–258. [CrossRef] 115. Carroll, F.I.; Brine, G.A.; Boldt, K.G.; Cone, E.J.; Yousefnejad, D.; Bruce, V.; Aupel, D.; Buchwald, W.F. Phencyclidine metabolism: resolution, structure, and biological activity of the isomers of the hydroxy metabolite, 4-phenyl-4-(1-piperidinyl)cyclohexanol. J. Med. Chem. 1981, 20, 1047–1051. [CrossRef] 116. Cook, C.E.; Perez-Reyes, M.; Jeffcoat, A.R.; Brine, D.R. Phencyclidine disposition in humans after small doses of radiolabeled drug. Fed. Proc. 1983, 4, 2566–2569. 117. Huestis, M.A.; Mitchell, J.M.; Cone, E.J. Detection times of marijuana metabolites in urine by immunoassay and GC-MS. J. Anal. Toxicol. 1995, 19, 443–449. [CrossRef] 118. Abraham, T.T.; Lowe, R.H.; Pirnay, S.O.; Darwin, W.D.; Huesti, M.A. Simultaneous GC–EI-MS determination of δ9-tetrahydrocannabinol, 11-hydroxy-δ9-tetrahydrocannabinol, and 11-nor-9-carboxy-δ9- tetrahydrocannabinol in human urine following tandem enzyme-alkaline hydrolysis. J. Anal. Toxicol. 2007, 41, 477–485. [CrossRef][PubMed] 119. Portoghese, P.; Sultana, M.; Nagase, H.; Takemon, A.E. Application of the message-address concept in the design of highly potent and selective. Delta Opioid receptor antagonists. J. Med. Chem. 1988, 31, 281–282. [PubMed]
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