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Analgesics - antipyretics = „weak“ analgesics = non-opioid analgesics Most of them also ••non-steroidal anti-inflamatory drugs (NSAIDs) antirheumatics Oldřich Farsa 2011 Metabolism of eicosanoids O Oarachidonic acid OH2 =<ul style="display: flex;"><li style="flex:1">C O </li><li style="flex:1">R1 </li></ul>OH OH R2 <ul style="display: flex;"><li style="flex:1">R2 </li><li style="flex:1">O</li></ul>CH3 C O P O H2 ON+ CH3 CH3 glucocorticoids inhibitors of phspholipase A2 prostaglandins sythesis = = "weak" COOH analgesics + lipoxygenase inhibitors + NSAIDs arachidonic acid cyclooxygenases (COX1 + COX2) lipoxygenase OOH COOH OO COOH 5-hydroperoxy-6-trans-8,11,14-cis-eikosatetraenoic acid PG G2 OOH (5-HPETE) cyklooxygenases prostacyklin synthase PG I2 = prostacyklin endothelium cells tromboxan synthase PG H2 TX A2 LT A4 isomerases trombocytes PG D2 PG E2 LT C4 LT B4 PG F2 αall the cells LT D4 LT E4 Effects of prostaglandins Prostaglandin E, F2α : ache, fewer, inflammation, sekretion of HCl↓, stomach mucosa capilaries dilatation, contraction of uterus, kidneys: excretion of Na+ and H2O ↑ Prostacyclin (prostaglandin I ): vasodilatation, platelets aggregation inhibition 2Tromboxan: vasokonstriction, platelets aggregation activation Leukotriens: alergic reactions (e.g. asthma bronchiale) Cyklooxygenases (= prostaglandin G/H synthases) COX1 Constitutive: in all the tissues Functions: •••protection of stomach mucosa (vasodilatation) diuresis platelets aggregation (TXA) COX2 Philipp Needlemann inventor of COX isoenzymes Constitutive: kidneys, brain (co-localized with cyclins D1 and E) Inducible: macrophages, neutrophfils, fibroblasts, endothelium cells Functions: (1989) vasodilatation (PG I ) •••2porod (děložní stahy) childbirth (uterus contractions) inflammation processes COX3 ?? (= COX1b; brain ?) Classification of COX inhibitors (antipyretics, NSAIDs) Non-selective (COX1 + COX2) ••••Anilides Salicylates Phenamates Aryl- and heteroaryl alkanoic acids •Aryl- and heteroaryl acetic acids <ul style="display: flex;"><li style="flex:1">•</li><li style="flex:1">Aryl- and heteroaryl propionic acids </li></ul>•••Oxicames 1,2-Dihydropyrazolidine-3-ones 2,5-Pyrazolidinediones Selective (COX1<COX2): nimesulide Specific (COX2) •Coxibes Anilides <ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul>O OH paracetamol acetaminophen 4-(acetylamino)phenol phenacetin N-(4-ethoxyphenyl)acetamide acetanilide <ul style="display: flex;"><li style="flex:1">(</li><li style="flex:1">)</li></ul>N-phenylacetamide nephrotoxicity Dinyl® - analg. 1886: Antifebrin® para-(acetylamino)phenol p-(acetylamino)phenol Paralen , Panadol …. mixture with caffeine, aminophenazone and barbiturates Paracetamol •inhibits COX only in CNS (COX3 ?) not in periphery ⇒ •effects: analgesic, antipyretic (not antiinflamatory, antirheumatic) Použití ve směsích s(e) Usage in mixtures with •codeine, caffeine ⇒ effect enhancement (Korylan tbl.®, <ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul>Panadol tbl.®, Efferalgan codein tbl. eff.®) •••expectorants (guajfenesin, terpin) antitussives (dextromethorphan) H -antihistaminines (pheniramine, chlorphenamine, OH 1dimenhydrinate, promethazin, doxylamin) together with α-sympatomimetics (phenylefrine, pseudoephedrine) •••spasmolytics (pitophenon) myorelaxants (chlorzoxan, carisoprodol) NSAID (acetylsalicylic acid, propyphenazon – Valetol®) Metabolism of paracetamol Ourine O O O 2% urine S HO HO O OH O<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">42 % </li><li style="flex:1">52 % </li></ul>urine conjugation conjugation <ul style="display: flex;"><li style="flex:1">HO </li><li style="flex:1">OH </li></ul><ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">O</li></ul>NO CH3 paracetamol sulfate CH3 CH3 paracetamol glucuronide 4 % cytochrome P-450 RS R-SH (glutahione, N-acetylcysteine) OH N ONR-SH = glutathion ⇒ ⇒ merkapturic acid <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">CH3 </li><li style="flex:1">CH3 </li></ul><ul style="display: flex;"><li style="flex:1">N-acetyl-p-benzoquinoneimine </li><li style="flex:1">urine </li></ul>N-(4-oxocyclohexa-2,5-diene-1-ylidene)acetamide NAPQI HEPATOTOXIC Thiols detoxicating N-acetyl-p-benzoquinoneimine γ − Glu-Cys-Gly HS OH O O<ul style="display: flex;"><li style="flex:1">HO </li><li style="flex:1">N</li></ul>H O<ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">N</li></ul><ul style="display: flex;"><li style="flex:1">H</li><li style="flex:1">H</li><li style="flex:1">OH </li></ul>glutathione SH O OH <ul style="display: flex;"><li style="flex:1">H3C </li><li style="flex:1">N</li></ul>HON-acetyl-L-cysteine mucolytic ACC®, Mucobene® Synthesis of paracetamol OH OH Sn CH3COOH Morse, Chem. Ber. 11, 232 (1878) <ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul>NO2 CH3 OH O NO2 H3C 2-nitrophenol OH OH OOH OH H3C <ul style="display: flex;"><li style="flex:1">HNO3 </li><li style="flex:1">O</li></ul>Fe, HCl <ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul>NO2 NH2 CH3 4-(acetylamino)phenol phenol 4-nitrophenol 4-aminophenol Propacetamol – paracetamol prodrug •for intravenous application O Cl + H N O<ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul>CH3 4-(acetylamino)phenyl-N,N-diethylglycinate hydrochloride 2-[4-(acetylamino)phenoxy]-N,N-diethyl-2-oxoethaneaminium chloride propacetamol hydrochloreid Pro-Dafalgan® (UPSA Laboratoires) O N O HOOesterase H2O N+HO <ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">HN </li><li style="flex:1">O</li></ul>CH3 CH3 Salicylates OOO H3C H3C HO HO <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul><ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul>HO Ohydrolýza oxidace <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">CH3 </li></ul>OOH O<ul style="display: flex;"><li style="flex:1">HO </li><li style="flex:1">OH </li></ul>salicylic acid 2-hydroxybenzoová kys. salicin acetylosalicylic acid 2-acetoxybenzoic acid (2-hydroxymethylphenyl)- β-D-glucopyranoside 1838 Piria: the first synthesis since 1878 used as antipyretic and antirheumatic 1827 Leroux: isolation from willow 1897 Felix Hoffmann - industrial synthesis 1899 – Aspirin® (Bayer) <ul style="display: flex;"><li style="flex:1">Felix Hoffmann </li><li style="flex:1">Sir John R. Vane </li></ul>Effects of acetylosalicylic acid „Wanted“: <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul>•••••antipyretic <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">CH3 </li></ul>analgesic Oanti-inflamatory antirheumatic ®antithrombotic (↓ platelets aggregation) – Anopyrin „Unwanted“: <ul style="display: flex;"><li style="flex:1">•</li><li style="flex:1">ulcerogenic </li></ul>•Rey syndrom in childern after viral infection (hepatopathy, encefalopathy) ⇒ contra-indication in childern •bleeding (e.g. from nose - ↓ platelets aggregation) Intoxication = „salicylism“ – infliction of CNS (psychical malfunctios, buzz in ears, dizzines, deafness), methabolic acidosis Mechanis of action of acetylosalicylic acid (ASA) •irreversible inhibition od cyclooxygenases by acetylation of serine rest Ser <ul style="display: flex;"><li style="flex:1">HO </li><li style="flex:1">O</li></ul>O<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">CH3 </li></ul><ul style="display: flex;"><li style="flex:1">H3C </li><li style="flex:1">O</li></ul>+OH COX +<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>COX NH2 O NH2 <ul style="display: flex;"><li style="flex:1">HO </li><li style="flex:1">O</li></ul>OH +<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul>O<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">CH3 </li></ul>Metabolism of ASA proceeds in liver HO HO O OH O O••O ASA all metabolits are excreted t1/2= 15 min. <ul style="display: flex;"><li style="flex:1">HO </li><li style="flex:1">OH </li></ul>by urine O1-salicyoylglucuronic acid 5 % <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul>OH <ul style="display: flex;"><li style="flex:1">glucuronation </li><li style="flex:1">CH3COOH </li></ul>+O OH OHO HO salicylic acid. 10 % Oconjugation with Gly O O OH O NH HO OH OH hydroxylation O1-(2-carboxyphenyl)glucuronic acid 10 % salicyluric acid (N-salicyoylglycine) <ul style="display: flex;"><li style="flex:1">75 % </li><li style="flex:1">O</li><li style="flex:1">OH </li></ul>OH HO gentisic acid < 1 % Syntheses of ASA <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul>OH <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul>OGerhardt, Justus Liebigs Ann. Chem. 87, 164 (1853) Gilm, Justus Liebigs Ann. Chem. 112, 181 (1859) Kraut, Justus Liebigs Ann. Chem. 150, 10 (1869) <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li><li style="flex:1">H3C </li></ul>Cl CH3 O H3C H3C <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul>OH OO<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">OH </li></ul><ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>Felix Hoffmann CH3 Other salicylates CH3 CH3 CH3 O O<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>O O F O<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">Al </li><li style="flex:1">Al </li><li style="flex:1">Al </li></ul>OH O O<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>F OH <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li><li style="flex:1">O</li></ul>O CH3 CH3 2',4'-difluoro-4-hydroxy-1,1'-biphenyl-3-carboxylic acid pentakis(acetylosalicyoyloxy)trialuminium dioxide <ul style="display: flex;"><li style="flex:1">aloxiprin </li><li style="flex:1">diflunisal </li></ul><ul style="display: flex;"><li style="flex:1">Superpyrin® </li><li style="flex:1">Unisal® tbl. </li></ul>Anthranilic acid derivatives – phenamates = substition derivatives of 2-phenylaminobenzooic acid derived from salicylates by substitution of hydroxy group with •(phenyl)amino moiety OH OR3 HNR1 R2 ••••aromatic amino acids substituted on the aniline ring only inhibit both COX1 and COX2 (selectivity?; COX3?) analgesics, antipyretics, antimigrenics, anti-inflammatory Phenamates OH OR3 HNR1 R2 <ul style="display: flex;"><li style="flex:1">R1 </li><li style="flex:1">R2 </li></ul><ul style="display: flex;"><li style="flex:1">R3 Chemica name </li><li style="flex:1">INN / preparation </li></ul>2-(2,3-dimethylphenylamino)- benzoic acid -CH3 -CH3 -H mephenamic acid 2-(2,6-dichloro-3- methylphenylamino)benzoic acid -Cl -CH3 -Cl -CH3 -Cl -H meclophenamic acid 2-(3-chloro-2- methylphenylamino)benzoic acid tolphenamic acid Migea rapid® 2-(3-trifluoromethylphenylamino)benzoic acid <ul style="display: flex;"><li style="flex:1">-H </li><li style="flex:1">-CF3 -H </li></ul>fluphenamic acid Tolphenamic acid Synthesis K+ OH NO<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>NH2 HN CH3 Cl Br O+1.(CH3COO)2Cu, DMF 2. H+ H3C Cl Kaltenbronn J.S. et al., Arzneim. Forsch 33, 621-627 (1983) Selectivity against COXs IC (COX1) 50 IC (COX 2) = 10 50 Grossmann C. J. et al., Inflammation Res. 44, 253-257 (1995) Niflumic acid and its esters F F<ul style="display: flex;"><li style="flex:1">F</li><li style="flex:1">F</li></ul>F FHN HNC NO OOH OH 2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid fluphenamic acid niflumic acid •isosteric substitution benzene ⇒ pyridine, or –CH= ⇒ -N= ••inhibit both COX1 and COX2 anti-inflamatory, antirheumatics; usually topically administered Niflumic acid and its esters •esters are prodrugs which can better penetrate through the skin R2-{ [(3-trifluormethyl)phenyl]amino}nicotinic acid Hniflumic acid Niflugel®, Nifluril® F FF-||- 2-(morpholine-4-yl)ethylester HN Nmorniflumate N OO O R -||- 1-oxo-2-(3H)-benzofurane-3-ylester talniflumate OOAryl- and heteroarylalkanoic acids Structure-activity relationships (SAR) •the aliphatic part of the molecule is more specific for the effect than the aromatic one OARY >O<ul style="display: flex;"><li style="flex:1">ARY </li><li style="flex:1">O</li></ul><ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">ARY </li></ul>O= = >OH ARY OH ARY OH <ul style="display: flex;"><li style="flex:1">H3C </li><li style="flex:1">OH </li></ul>OH ARY = aryl, heteroaryl Aryl- and heteroarylacetic acids and their functional derivatives O H2C R Y R = aryl or heteroaryl Y = OH, NHOH, NHR, OCH2COOH, or other •••antirheumatics, anti-inflamatory, analgesics, antipyretics inhibition of both COX1 and COX2 adverse effects (AE) like in salicylates Aryl- and heteroarylacetic acids and their functional derivatives O(fenacs) H3C O O R O<ul style="display: flex;"><li style="flex:1">Cl </li><li style="flex:1">Cl </li></ul>NH Cl N CH3 <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>RR = H R = H {2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid diclofenac indomethacin •• •<ul style="display: flex;"><li style="flex:1">used since 1975 </li><li style="flex:1">used since 1963 </li></ul><ul style="display: flex;"><li style="flex:1">now mainly topically </li><li style="flex:1">Voltaren®, Veral®, Myogit®, </li></ul>Dicloreum® Indobene® cps, Bonidon® gel, Elmetacin® spr R= OCH2COOH {2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid carboxymethylester R = OCH2COOH [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid caboxymethylester aceclofenac acemetacin Heteroarylacetic acids and their derivatives O O HN O N O<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li><li style="flex:1">N</li></ul><ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">CH3 </li><li style="flex:1">O</li></ul>H3C N O<ul style="display: flex;"><li style="flex:1">H3C </li><li style="flex:1">CH3 </li></ul>Cl proglumetacin Cl Cl N NNSOH OH O O[3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-yl]acetic acid [4-(4-chlorophenyl)-2-phenyl-1,3-thiazole-5-yl]acetic acid <ul style="display: flex;"><li style="flex:1">fentiazac </li><li style="flex:1">lonazolac </li></ul>•isosteres Aryl- a heteroarylacetic acids CH3 N CH3 O O

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