Ali Gamal Ahmed Al Kaf.Pdf

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Prodrug Univesity.Faculty  studies  chemicalentity, the prodrug. modifications chemical  which givespharmacologic the response. biotransformation undergoes which prodrug  considered  site  American Medicinal Chemistry Journal. Associate prof.Associate Journal. Chemistry Medicinal American prodrugs. were 2002 approximately and prodrugs, promoted urnl, 5 Currently, drug The coined first was prodrug term The can barrier The There response pharmacologic gives drug The of action. “eredipity is

fco ta lmt is piu etrn it ti site this into entering optimum its limits that factor a as this concept this is only identified only barrier. – 7% of be of Pharmacy.Medicinal ChemistryDepartment.

h dus prvd olwd can worldwide approved drugs the overcome by of by : Dr a biologically activity compound activity biologically a

defining the term "DRUG LATENIATION" "DRUG term the defining Introduction Ai Gamal .Ali as 15 a prodrug after extensive drug metabolism drug extensive after prodrug a % by of hmcly ikn promoiety linking chemically all new drugs approved drugs new all by Al Albert Albert kfEioil or member board -kaf-Editorial by

binding with receptor with binding to in ees te aet drug parent the release 1958 of . Med.Chem. apr 15) has (1959) Harper be to classified classified form a new a form in 2001 and 2001 to “aaa as at form the the the the as of is

Prodrug

Prodrug 

pharmacological activity activity pharmacological metabolicinactivation (e compound must  Ex susceptible not readilyeliminated and half-life Due biological long metabolism. having solubility  Ex synthesized and designed are  an active drug by a metabolic biotransformation a pharmacological inactive compound that convertedis to

g Initial definitionsInitial : : : Cocaine. heroin.and : Insulin. Antedrug ad Drugs Hard Drugs Soft

steroidal drug thattopically used to to hi avoiding their

be susceptible :compounds that are designed and synthesizedand designed are that :compounds Tee r the are These : cmons aig ih ii solubility lipid high having compounds : due

to to to to nontoxic products. lack eaoim te hv hg efficiency high have they metabolism, metabolic locally of as prodrug: metabolism. opposite

ACTIVE and when enter the systemiccirculation the enter when and or to chemical transformation treat someallergic condition)

compounds that readily undergo readily that compounds of prodrugs.

hs compounds These . or to ih water high exert their exerttheir to inactive but less to

Prodrug

Type II Type II Type I Type I Type

Classification Classification prodrugsof Extracellular Extracellular Extracellular Intracellular Intracellular Converting Converting site

Subtype Type IIA Type IIB Type IB

Metabolic tissues tissues Metabolic (liver/lung etc) (liver/lung conversion location location of Therapeutic tissues/cells tissues/cells circulation Systemic GI fluid fluid GI Tissue target target

Sulfasalazine Fosphenytoin 5 , Cyclophosph Loperamide Zidovudine - Bambuterol Captopril Examples Flurouracil amide oxide oxide

, ,

Prodrug  unattractive have drugs when used physicochemical properties ((undesirable properties)). are Prodrugs 9. 8. 7. 6. 5. 4. 3. 2. 1. Why use prodrugs? Pain at thesite of injection. Not site-specific. Rapid absorption/excretion. Good substrate for first-pass metabolism. formulation problems. poor patient acceptability. Chemical instability. Low lipophilicity. Poorsolubility. aqueous

Prodrug pharmacologically inactive. • h drug The groups that are chemically or enzymatically labile, • (bio)pharmaceutical • The drug andpromoietyThe are covalently linked bioreversiblevia limitation – rmit i te rdu ta i typically is that prodrug the is promoiety of a parent drug that prevents optimal optimal prevents that drug parent a

Prodrug Concept or pharmacokinetic performance.

pharmacokineticproperties. biopharmaceutical or biopharmaceutical physicochemical, active agents to improve of pharmacologically structureto the modify groupA functionalused Promoiety

Ideal Property Of Prodrug:

1) The prodrug should be less toxic than the drug.

2) The pordrug should be inactive or significantly less active than the parant drug. Prodrug 3) The rate formation of drug from the prodrug should be rapid eough to aitai the drug coc. With its therapeutic window. 4) The metabolites from the carrier should be non-toxic or have a low degree of toxicity.

5) The prodrug should be site specific.

Prodrug ·Toxicitymay conjugates. ·Formation which duetois : problemThe associated with prodrug itsis design toxicity of depletion causes which stage activation its during glutathione Te rdu mgt osm a ia cl cnttet such constituent cell vital a consume might prodrug ·The toxic into metabolite. converted is which conjugate drug and promoiety prodrug. LimitationOf Prodrug: of be nxetd eaoie rm h ttl drug total the from metabolite unexpected

due

to inert carrier generated carrier inert by cleavage

as of

Prodrug

promoiety Prodrugs according to functional groups: Prodrug

Common functional groups on parent drugs that are amenable to prodrug design (shown in green). Prodrug A. A. which prodrug double The  steps(enzymatically B. B. directly between species. crir connected carrier drugs. Double ProdrugDouble bipartate : bipartate rprie rdu : prodrug tripartite comprised of one carriercomprisedof one attached to drug.  to Carrier linkedinto:prodrugsubdivided drug is promoiety. transformed

molecule and promoietyand molecule . in which the parent drug parent the which Relateddefinitions or to is pro-prodrug : or lne that linker a a biologically inactive molecule molecule inactive biologically a

chemically) there in is vivo cnetr group connector a is to connected is

h active the attached in two to to

Prodrug

• • • • • • Are stable thedosagein form. Are easily preparedand inexpensive. Are biodegradable, inert, and nonimmunogenic. Minimize host toxicity. Localize the drug at thesite of action. Protect the druguntil reachesit the site of action. Ideal Drug CarriersIdeal Drug

Prodrug •

to relative lipophilicity increased diesterification prodrug a is HCL Dipivefrin The The agent a) Examples :

move across membranethe

Dipiveferin HCL of

Dipiveferin HCl use in the treatment use in the Carboxylic acid and alcoholsandacid Carboxylic of epinephrine and pivalic and epinephrine acid.

: of to of

Esterase pnprn formed epinephrine epinephrine allows the agent the allows epinephrine the the eye . applied easily when of open angle glaucoma open angle . the

Pivalic acid :

Epinephrine by the Prodrug • h muh and mouth the hydrophopic The solubility, water palmitateester reduced with prodrug A receptors. b) Examples : chloramphenicol palmitate : chloramphenicol palmitate Carboxylic acid and alcohols and acid Carboxylic

dose not dissolve not dose

therefore

oe not dose

Esterase to any appreciable extentappreciableany

interact

chloramphenicol :

palmitic Acid palmitic Acid ih taste with

+ in in

Prodrug • Hetacillin effect The variety converted Hetacillin : absorption . basicity basicity Examples : of of

organisms. Hetacillin s bt-atm Htcli i a ciiy bt is but activity, a is Hetacillin beta-lactam. a is h aie n there and amine the

by of the body the

forming

to the

Amines Amines ampicillin

water anc bs is base Mannich by , which is active against a a against active is which , ces lppiiiy and lipophilicity icrease

Acetone to lower

ampicillin

the the Prodrug • sulfasalazine • treatment the (ulcerative in used is Sulfasalazine :

Anaerobic bacteria in the lower bowel metabolically reduce metabolically bowel lower the in bacteria Anaerobic Examples : colitis). to the therapeuticthe agent

Azo reductase

Azo linkage Azo linkage of

inflammatory bowel disease disease bowel inflammatory 5-aminosalicylic 5-aminosalicylic acid.

Prodrug • agent. converted to formaldehyde ,which act as anantibacterial Methanamine is prodrug Methenamine : Examples : N N N N

Carbonyl compounds compoundsCarbonyl Acidic urine pH

in acidic acidic in methamine pH , is 6 H O H + 4 NH 3 Prodrug • in the intestines. passes occurs absorption .subsequent agent class this with associated and functionality normally irritation the producing without acidicstomch the through no contains Nabumetone oxidative activation. : Nabumetone new a generates enzymes, and metabolite expectedthe being active agent. modification acts This which compound, itself. modification molecular compound a from result Which Examples :

Nabumetone

Bioprecursor Prodrug Bioprecursor

NAD (Relafen) (NSAID) as sbtae fr h metabolizing the for substrates a

oxidation

rdu ta requires that prodrug

Active Form of h active the

Prodrug • that requiresReduction  effective in killing bacteria.  C: Mitomycine to order in synthetised were quinones heterocylic bis-alkylating Potential nucleoside. guanine a for specific N-alkylations two

Examples : ioyie C Mitomycine is explore antitumoralthe activities potent a N crosslinker DNA Mutamycin

Bioprecursor Prodrug Bioprecursor

required a a required of the the ®

Ti cosik a shown has crosslink This . eutv atvto followed activation reductive quinone atnolsi agent) (antineoplastic of bacteria. to hydroquinone.

prodrug to

be by

Prodrug • that requiresReduction C: Mitomycine H H 3 2 H H Examples : electron withdrawing A quinone - C N 3 2 Further alkylation C N OH OH O O H N N H 2 N DNA O OMe NH O NH Mutamycin Reduction Bioprecursor Prodrug

H H of 3 2 H H C N 3 2 the the electron donating A - hydroquinone C N Electrophile ®

OH OH

OH OH quinone atnolsi agent) (antineoplastic

H + N N H 2 DNA N O OMe NH O NH to -NH -OCH -CO hydroquinone. 3 2 3 H H H H

3 2 3 2 C N C N OH OH

H -H+ prodrug + N N H H 2 2 N N O H+ O O NH O NH Prodrug • of  an   agent) (antiviral phosphorylation. : Vidarabine rpopae r-T (atv fr). hs cie om s both is form active This form)). ((active ara-ATP triphosphate Examples : ara-ATPdATPinhibits competitively vidarabine works

inhibitor a and substrate faulty by viral DNA. interfering the with synthesis is eunily phosphorylated sequentially Bioprecursor Prodrug

of viral DNA polymerase.

rdu ta requires that prodrug leading leading of viral DNA. by to kinases the formationthe to the the Prodrug • iaaie (niia agent) (antiviral : Vidarabine phosphorylation. Examples : Bioprecursor Prodrug Bioprecursor

rdu ta requires that prodrug Prodrug • as togethercoupled comprises Prodrug are called Examples :

the carrier for carrier as mutual mutual prodrug. to

the form a single molecules such that each act each that such molecules single a form of Mutual Prodrug Mutual other prodrug other w pamclgcly cie agents active pharmacologically two

of two active compounds active two Prodrug •

linkage  prostate.the  Estramustine: Nornitrogen mustarda weakis alkylatingagent 17

Prodrug Examples : -alphaestradiol slow prostatecell growth Usedfor the Cl N O Emcyt Phosphate Sodium Estermustine is O hydrolyzed. is ® - Pharmacia & Upjohn & Pharmacia - selectively taken selectively H 3 C OPO

treatmentof progressive carcinoma of 3 Na 2 Mutual Prodrug Mutual up into estrogeninto OH Nornitrogen mustard Nornitrogen Cl H Cl 3 C NH

receptor positive cells then then cells positive receptor OH

Carbon dioxide Carbon and phosphate Sodium Actual alkylating species alkylating Actual Cl NH+Cl- Aziridine Prodrug

DIPIVEFRIN HCl

Hetacin-K

0.1 solution %, Alcon® ophthalmic

Chloramphenicol Palmitate Chloramphenicol KLORAN SUSPENSION KLORAN

125 Relafen Relafen mg ofmg

con ® tai ns . Prodrug

Man

( methenamine de lamine )

® Sultamicillin Sultamicillin

(Sultamacillin) ®

Prodrug • drug) Ex prodrugs on solubility aqueous low the E.g. • • (a) PHARMACEUTICAL APPLICATIONS coated • • e .g; Ethyle .g; mercaptan which is afoul smelling liquid, is converted in to its

Reduction Enhancement Improvement Enhancement Improvement Formaldehyde : neto. hs can This injection. to prevent hydrolysis of such agents.such E.g. 2-phosphate ester Chloramphenicol Palmita Chloramphenicol of Ex: Ex: drug drug ester ,which b.p. has higher odorlessand pain of of of Parent drug Parent drug of is taste. odor. chemicalstability drug solubility and dissolution rate (hydrophilicity rate dissolution and solubility drug used used on injection. as APPLICATIONS be in prodrug the stomach. the overcome of clindamycin Hcl Hcl clindamycin (( of

methenamine

drug.

by (( urinary tract urinary antiseptic use

of of )) clindamycin is prodrug oe ae soIubIe water more

in responsible for pain pain for responsible teester h form the

)) of . . enteric of

Prodrug

• • • • • (b) PHARMACOKINETIC APPLICATIONS drug site-specificdelivery(drug targeting). Reduction Prolongation Prevention Enhancement

of of toxicity. of presystemicmetabolism. of duration bioavailability (lipophilicity). of action. Prodrug Examplesof Prodrugs for improved lipophilicity or permeability lipophilicity

Prodrug Prodrug Prodrug Prodrug Examplesof Prodrugs for improved aqueous solubility

Prodrug Prodrug Prodrug Examplesof Prodrugs for improved parenteraladministration

Prodrug Prodrug Prodrug Examplesof Prodrugs to exploit carrier-mediatedabsorption

Prodrug Prodrug Examplesof Prodrugs for improved ophthalmicand dermal delivery

Prodrug Prodrug Examples Prodrugs of for other purposes other

Prodrug Prodrug not not for other endogenous enzymes III II expressed poorly enzyme prodrug-activating The I. but half-lifeThe VII. nonexpressing (bystandercells killingeffect) VI V. prodrugThe should havelow cytotoxicity and the drug cytotoxicityhigh IV enzyme incorporated. II. administera nontoxic prodrug which a issubstrate for the exogenous

I. . prodrug-activatingThe enzyme musthave high catalytic activity incorporate a prodrug-activating enzyme intotarget a tumor cell. . Theprodrug must . The prodrug must prodrug The . Te ciae du should drug activated The . short enough For selective activation of prodrugs in tumor cells Two steps Criteria for with Success Enzyme-Prodrug Therapies

Prodrug Therapies ((cancer therapies)) of to the active drug active the avoid out leaking be be able a good substrate for the incorporated enzyme and enzymeincorporated the forsubstrate good a to cross tumor cell membranes be is is ihr nonhuman either long enough for bystander killing effectbystanderforkilling enough long ihy diffusable highly of

tumor cells or to hmn protein human a il neighboring kill

Prodrug 3. Potentialfor active leakof the back drug 2. Complexity systemthe two-phase of i.v and administration rejectionantibody-enzyme. and conjugate1. Immunogenicity of Disadvantages 5. 4. 3. 2. 1. Advantages conversionprodrugthe reachesit of totumorwhen cell. thedrug the conjugated enzymeThe antibodyatcellsurfacetumor the withcatalyzes the the conjugateprodrugisadministered. the tissues, cleared normal and is from blood the excessthe Aftercelland .antibody-enzyme accumulatedthe tumor the has on 2 groupprod off ofthe rug administered nextin the phase. forchosen enzymeThe the conjugate toused cleave thatbe isone will carrier the cells.Thetargeted been has antibodyused forcell. tumor the particular antibody-enzymeAn conjugateisadministered to thesurfacetumor binds of the which One: Phase l. (ADEPT)TherapyProdrug (a)Enzyme Directed Antibody .Phase Two:.Phase Concentrates at thesite the drug of action. Demonstrated toeffective be at clinicallevel.the isatreleased thesite The drug of action. Eachconverts enzyme molecule manyprodrugMolecules. Increased for selectivity targeted cell.

An approachfor site-specific delivery ofcancerdrugs.

Prodrug Prodrug activatecells These prodrug the under  (GDEPT) TherapyProdrug Enzyme Gene-Directed (c) prostate cancer cells. catalyzed Found catalytic(abzyme)antibody can ( Antibody bound. could prodrug the where site known not reaction a catalyzes abzyme the Ideally, b) (ADAPT)Antibody-DirectedTherapyProdrug Abzyme A gene encoding the prodrug-activating enzyme prodrug-activating the encoding gene A Instead the control the to by of

38 be sn a rdu-ciaig nye a uaie prodrug¬activating humanized a enzyme, prodrug-activating a using any enzyme. knownsss human C2 catalyzes sequential retro-aldol and and retro-aldol sequential catalyzes C2 long-lived long-lived of tumor-selectivepromoters in vivo, be be to as activated used. used. activate prodrugs selectively, and prodrugs activate

in DEPT.

at or the tumor cell where the abzyme the where cell tumor the

by is to expressed viral transfection. re occur tro-Mich ael reactions not not reactions ael tro-Mich

In humans, humans, in target cancer cells cells cancer target to kill colon and and colon kill so the only only the is

Prodrug Prodrug Chemistry. New Age Publishers, New Delhi, RaoNadendla4. Rama and PharmaceuticalChemistry. - 11 2004 2.Wilson and Assoc.; USA; Prodrugsand Analogs; Ed. E.B.Roche; Am Pharm. 3. Design ofBiopharmaceutical Properties Through 933 Jone Thomas.1.Gareth Medicinal Chemistry.2 5 . Ashutosh Kar.Ashutosh Medicinal Chemistry.-4

; Wiley &Sons Ltd, 980 . . Gisvold’s 1977 References : . . , . Textbook of Organic Medicinal 2007 Priciples Priciples of Organic Medicinal 1

;p 464 .

ed. -New -New York. ed. nd Edition. Edition. -india. 2005 ; 2007 322 . ;

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