Module 1 - Organic Medicinals PDF

ORGANIC MEDICINALS ------------------------------------------------------------------------ ORGANIC MEDICIAL – study of pharmaceutical chemistry o Inverse Agonist – drug that binds to receptor; does not focused in discovers synthesis and design of bioactive molecules...

ORGANIC MEDICINALS ------------------------------------------------------------------------ ORGANIC MEDICIAL – study of pharmaceutical chemistry o Inverse Agonist – drug that binds to receptor; does not focused in discovers synthesis and design of bioactive molecules activate receptor  prevents endogenous ligand from binding I. PHARMACODYNAMICS  Constitutional Activity – activity of a receptor even in the absence of endogenous ligand  study of how drugs interact with its target; (enzymes: proteins, lipids; receptors: nucleic acids) receptors (active) receptors (inactive) agonist antagonist Inverse agonist partial agonist I. ENZYMES AS DRUG TARGETS  Desensitization – when agonist is bound to its receptor for a  Active Site Inhibitors long period of time; shape of receptor is altered even if o Reversible Inhibitors – “competitive inhibitors”; drug is occupied designed similar to endogenous substrate which competes to active site  Sensitization – when antagonist is bound to its receptor for a o Irreversible Inhibitors – drug that forms a covalent bond to long period of time an amino acid residue in active site; permanent; (ex.  Consequences of desensitization and sensitization: fluorophosphates [P=O] + AchE; disulfiram + aldehyde o Tolerance – situation where increased doses of a drug are dehydrogenase) required over time to achieve same effect; due to increased number of receptor  Allosteric Site Inhibitors – drug that binds to a site other than where endogenous ligand binds; will cause induced fit of active o Dependence – related to body’s ability to adapt to presence site  active site will no longer be recognizable to ligand; of a drug; withdrawal symptoms occur as result of abnormal “non-competitive inhibition” levels of target receptor; if drug is stopped, receptors become available  supersensitive to normal levels of  Uncompetitive Inhibitor – drug binds to enzyme-substrate endogenous ligands complex III. NUCLEIC ACIDS AS DRUG TARGETS II. RECEPTORS AS DRUG TARGETS  Intercalating Agents – contain a planar, heteroatomic rings  Receptor – any part of a cell, usually protein, found in cell that slips in between; membrane or in cytoplasm to which drug interacts to elicit a DNA base pairs  interrupt DNA replication and transcription response  cell death o Agonist – drug designed similar to an endogenous ligand  Requirements: (1) correct functional groups; (2) correct  Topoisomerase Poisons – drugs stabilize normally cleavable orientation; (3) correct site complex between topoisomerase and DNA  Allosteric Modulators (indirect agonist effects) – drug o Podophyllotoxins – topoisomerase II binds to site other than where ligand normally binds (ex. o Camptothecin – topoisomerase I benzodiazepines – GABA receptors; galantamine – o Nonintercalating Agents nicotinic receptors)  Alkylating Agents – electrophilic agents that form bonds to o Antagonist – drug that binds to receptor but does not nucleophiles found in DNA activate (N-7 of guanine)  intra and inter cross linking of DNA  Requirements/Strategies: (1) correct functional groups  o Nitrogen Mustards – chlormethine; chlorambucil; additional elimination; (2) bulkier ifosfamide  Other Mechanisms of: (1) allosteric modulator; (2) o Cyclophosphamide – most widely used alkylating agent; umbrella effect – binds to a site near binding site blocking metabolite: acrolein  administer a sulfhydryl donor such endogenous ligand from binding as mesna or N-acetylcysteine o Partial Agonist – drug similar to an agonist but does not elicit o Cisplatin – contain a central platinum atom full response  Chain Cutters – drugs that cuts DNA and prevents DNA ligase from repairing damage  Chain Terminators PAGE 1 OF 7 © MANOR REVIEW CENTER NOTES (K.L) II. PHARMACOKINETICS Monoamine Oxidase (MAO) o MAO-A – prefers serotonin, catecholamine and  study of journey of drug in body; ADME other amines (phenolic amines); adrenergic neurons I. ABSORPTION o MAO-B – prefers non-phenolic amines; brain  transfer of drug from site of administration to systemic o Reduction Reactions – less common pathway; aldehydes, circulation; drug must be sufficient polar to dissolve in ketone, azo, and nitro aqueous environment but must be sufficiently lipophilic to  Nitro (NO2)  amine (NH2) cross cell membrane  Azo (N≡N)  hydrazo (HN=NH)  2 amines (NH2, NH2)  Ionization affects absorption: ionized drug – unabsorbed;  Phase II Metabolism – conjugation reactions; addition of unionized drug – absorbed small, polar endogenous molecules to parent drug or phase I  pH of environment determines ionization: weak acid – metabolites; catalyzed by transferases unionized at acidic media; weak base – unionized at basic o Glucoronidation – most common phase II pathway media  Glucuronide – small, hydrophilic compound  Henderson-Hasselbach Equation  Source: UDFD – glucuronate 𝑏𝑎𝑠𝑒 𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑝𝐻 = 𝑝𝐾𝑎 + log [ ][ ]  Enzyme: glucuronosyl transferase 𝑎𝑐𝑖𝑑 𝑢𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 ∗ 𝑝𝐻 → 𝑖𝑜𝑛𝑖𝑧𝑒𝑑 = 𝑝𝐾𝑎 → 𝑢𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑  Gray Baby Syndrome – administration of chloramphenicol in neonates II. DISTRIBUTION o Sulfate Conjugation – prefers compounds containing  transfer of drug from blood to cell or interstitium; affected by phenolic groups plasma protein binding (albumin – acid drug; α-acid  Source: PAPS glycoprotein – basic drug)  Enzyme: sulphotransferases  Examples: methyldopa (similar with catecholamines),  Free Drug – acrive; Bound Drug – inactive terbutaline, albuterol, acetaminophen and phenacetin (p-aminophenol derivatives) III. METABOLISM o Amino Acid Conjugation – prefers compounds containg  “biotransformation”; modification of drug  more polar  carboxylic acid groups; glutamine and glycine conjugation; more excretable; formation of metabolites Hippuric Acid – first mammalian metabolite isolated  Phase I Metabolism – “functionalization reactions”; addition product of glycine conjugation of benzoic acid of functional group = more polar o Glutathione Conjugation o Hydrolysis Reaction – addition of H2O to break an ester or  Glutathione (glycine; cysteine; glutamine): tripeptide; amide bond; catalyzed by esterases and peptidases; good scavenger of free radicals; detoxification resistance to hydrolysis: Source: glutathione urcide > carbamate > amide > carbonate > thioester > ester Enzyme: transferase o Oxidation Reactions – most common pathway for drug o Acetyl Conjugation – prefers compounds containing amino metabolism; catalyzed by 3 enzymes acid  Dehydrogenases – uses a carrier (NAD+, FAD) as a H  Source: Acetyl-CoA acceptor  Enzyme: NAT (N-acetyltransferases); Asians – fast  Oxidases – uses an O atom as H acceptor acetylators; Caucasian – slow acetylator  Oxygenases – incorporation of O2 into a substrate o Methyl Conjugation – biosynthesis and metabolism of Dioxygenase – A + O2  AO2 (oxi) catecholamines Monooxygenase – A + O2  AO + H2O  Source: S-adenosyl methionine (SAM)  donor of methyl Examples:  Enzyme: methyl transferase CYP-450 Family (liver) – found in endoplasmic reticulum in liver; hemoproteins – contains heme; IV. EXCRETION prefer oxidation of carbon atoms (hydrocarbons   Renal Excretion – most common; nonpolar, unionized drugs = alcohols; alcohols  carboxylic acids) reabsorbed; polar, ionized = excreted o CYP 3A4 – family of enzymes responsible for  Biliary Excretion – liver metabolites  bile  small intestine metabolism of most drugs  feces o CYP 2D6 – metabolism of antidepressants; family where polymorphin is well studies (common)  Sweat, Tears, Saliva – pathways are not quantitatively significant Flavin-Dependent Monooxygenase (FMO) – prefer oxidation of N, P, S atoms; molybdenum as cofactor; found in ER of liver cells; uses FAD PAGE 2 OF 7 © MANOR REVIEW CENTER NOTES (K.L) III. ADRENERGIC DRUGS  Betaxolol (replace acetamido group with groups capable to H-bonding), Atenolol, Acebutolol, Metoprolol CATECHOLAMINES – catechol ring + alkylamine chain OH IV. CHOLINERGIC DRUGS *Dopamine – first synthesized I. BIOSYNTHESIS OF ACETYLCHOLINE (Ach) Catecholamine Acetyl CoA + choline –(choline acetyltransferase)-> Ach  Acetylcholine – rapidly hydrolyzed by acid catalysis; rapidly OH hydrolyzed in blood by esterases; offers no receptor I. BIOSYNTHESIS selectivity  2 Receptors: II. METABOLISM o Muscarinic Receptor – responds to muscarine; primarily  MAO – deamination found in cardiac and smooth muscles  COMT – methylation of one of –OH groups of catechol ring o Nicotinic Receptors – responds to nicotine; primarily found in synapses and neuromuscular junction III. SAR  3 Binding Groups: II. METABOLISM o OH groups – polar interactions with the receptor (H-  metabolized by enzyme acetylcholinesterase (AchE) bonding) o Aromatic Ring – Van-Der Waals interaction III. SAR o Ionizable N – ionic interactions O  Modifications: (1) attachment of bulky groups at N-atom of amine increases β activity, loss of α activity; (2) methyl NR3 substituents at α carbon increase α2 activity O IV. ADRENERGIC AGONISTS  General Agonists – activates both α and β receptors  Quaternary N – ionic interaction o Ephedrine – bronchodilator; component of Ma Huang;  Ethylene Bridge – 2C separation racemate: R,S and S,R stereoisomer  Acetoxy – receptor interaction; large substituents are not o Pseudoephedrine – S,S diasteriomer of ephedrine; used as allowed nasal decongestant  2 methyl substituents in quaternary N is important; third  Beta-2 Agonists – attachment of bulky groups large alkyl substituents is allowed but 2 or more bulky OH substituents lead to loss in cholinergic activity OH Isoprenaline B1, B2 agonist IV. INSTABILITY OF ACETYLCHOLINE N  interaction of N atom to carbonyl oxygen; neighboring effect V. DESIGN OF Ach ANALOGUES OH  Steric Shield – attachment of methyl group at α-carbon; (ex. o Group Shift Strategy – replacement of m-OH group with methacholine) hydroxymethyline; more resistant to COMT  Electronic Effect – change ester to carbamate (ex. carbachol) o Extension – attachment of a hydrocarbon chain or aromatic  Combination – Bethanecol ring to N-substituent; increases lipophilicity = longer duration of action VI. CHOLINERGIC AGONISTS  Muscarinic Antagonists – Pilocarpine – glaucoma V. ADRENERGIC BLOCKER  Nicotinic – Vernicline – smoking cessation  Alpha 1 Blockers: Prazosin (short duration); Terazosin, Ooxazosin (longer duration)  Beta Blocker o First Generation (β1, β2) – aryloxypropanolamine  + linking group; + aromatic group; Propanolol – prototype o Second Generation (selective B1 blocker)  Practolol – prototype; attachment of acetamido group to para position PAGE 3 OF 7 © MANOR REVIEW CENTER NOTES (K.L) VII. CHOLINERGIC ANTAGONISTS V. ANTIBACTERIALS  Muscarinic Antagonists – Atropine – prototype I. HISTORY o General Structure:  Carbolic Acid – phenol; Joseph Lister; antiseptic and sterilizing R2 agents for wards and hospital instruments  Salvarsan – compound 606, Arsphetamine; arsenic-containing O compound; red dye effective against streptococcal infections; R3 N R1 prodrug: converted to a suphonamide in vivo o Paul Erlich – father of chemotherapy; magic bullet – O chemical seen as bullet which could search out and destroy microorganism without adverse effect to host  selective o larger than methyl substituents are allowed; large toxicity substituents in ester group is allowed o Examples: II. ANTIMETABOLITES – sulfonamides or sulfa-drugs  Tropicamide & Cyclopentolate – dilates pupils  SAR – p-amino group is essential for activity and must be  Trihexyphenidyl & Benztropine – Parkinson’s Disease unsubstituted; aromatic group and sulphonamide group are  Pirenzepine – treatment of ulcers both required; suphonamide and amino group should be  Nicotinic Antagonists – neuromuscular blockers directly attached to aromatic ring; aromatic ring must be para- o Non-Depolarizing substituted  Tubocurarine – active principle of curare; two charged N  Modification – attach aromatic and heterocyclic rings  atoms are important in receptor interaction affects solubility  longer acting; leads to discovery of longer-  Atracurium, Miracurium – analogs of tubocuraraine; lack acting sulphonamides; (ex. Sulphadoxine [+Pyrimethamine = cardiac side effects; rapidly broken down in plasma  IV Fansidar – antimalarial agent) drip  Steriodal – “-curonium” ; steroid nucleus – separation between 2 charged N atoms V.A. CELL WALL SYNTHESIS INHIBITORS o Depolarizing Agents I. PENICILLINS act as agonist initially  persistent depolarization   Structure subsequent desensitization at end plate  relaxation o Nucleus – 6-aminopenicillanic acid; Beta Lactam Ring + thiazolidine VIII. ACETYLCHOLINESTERASE INHIBITORS o Side chain – acyl side chain  indirect cholinergic agonists  Biosynthesis – 2 amino acid precursors: valine, cysteine  Carbamates  SAR o Physostigmine – from calabar bean; used for glaucoma and o Bicyclic – half-open book; strain essential for activity myasthenia gravis o Amide is essential  side chain is important o Neostigmine & Pyridostigmine – N is permanently o S atom is common but not essential quaternary  permanently ionized = does not cross BBB = o Modifications: no CNS side effects  Attachment of electron withdrawing group  acid  Organophosphates – electrophilic  “P=O” resistance o Nerve Gases – Sarin, Tabun, Soman, VX  Attachment of bulky groups  β-lactamase resistance o Echothiophate – medicinally-used; glaucoma  Attachment of hydrophilic groups  ↑gram(-) activity o Parathion, Malathion – insecticides; prodrugs  Paraoxon,  Attachment of hydrophobic groups  ↑ gram(+) activity Malaoxon (P=O)  Penicillin Analogues o Isoxazoyl Penicillin – isoxazolyl ring; orally-taken; β- IX. ANTIDOTE TO ORGANOPHOSPHATE lactamase resistance  Requirement: strong nucleophile to cleave permanent P–O o Aminopenicillins – amino group: electron-withdrawing bond hydrophilic; orally-taken; broad-spectrum; β-lactamase  ProPAM (prodrug)  Pralidoxime (active) sensitive o Carboxypenicillins – carboxylic acid group: electron- withdrawing hydrophilic; orally taken; broad spectrum antibiotics o Ureidopenicillins – urea derivatives; broadest spectrum of activity; Piperacillin, Mezlocillin PAGE 4 OF 7 © MANOR REVIEW CENTER NOTES (K.L) II. CEPHALOSPORINS  Lincosamides – same properties with erythromycin;  Nucleus: 7-ACA Lincomycin – Streptomyces lincolnesis; Clindamycin – 7-aminocephalosporinic acid  β-lactam + dihydrothiazide ring chlorinated analogue of lincomycin III. OTHER BETA LACTAMS V.D. NUCLEIC ACID TRANSCRIPTION AND  Carbapenems o Notable Features: REPLICATION INHIBITORS  no sulfur atom; hydroxyethyl side chain  β-lactamase I. FLUOROQUINOLONES resistance; have broadest activity among β-lactam  Nalidixic Acid antibiotics  Enoxacin – fluorine atom in 6th position which increases Ertapenem & Micropenem – more resistant to potency and cellular uptake dehydropeptidase  Ciprofloxacin – addition of cyclopropyl  ↑broad-spectrum Imipenem – susceptible to dehydrogenase activity; replacement of N atom at 8th position which carbon  Monobactams – only have a single ring; unfused β-lactam; reduces side effects Aztreonam – chromobacterium violaceum II. RIFAMYCIN IV. BETA LACTAMASE INHIBITORS  Rifampicin – semisynthetic derivative of Rifamycin B – isolated  Clavulanic Acid – β-lactam ring is fused with oxazolidine ring; from Streptomyces mediterranei does not have an acylamino side chain  Penicillanic Acid Derivatives – Sulbactam & Tazobactam – III. METRONIDAZOLE – nitroimidazole derivative; antiprotozoal broader spectrum of activity against β-lactamases activity V. OTHER CELL WALL SYNTHESIS INHIBITORS VI. ANTIVIRALS – against DNA viruses  Cycloserine – from Streptomyces garyphalus; mimics structure I. DNA POLYMERASE INHIBITORS of D-alanine  Acyclovir – deoxyguanosine analogue  Bacitracin – Bacillus subtilis; binds to lipid carrier  Valacyclovir – L-valyl ester prodrug; deoxyguanosine analogue  Vancomycin – Streptomyces orientalis; glycopeptide  Desciclovir – prodrug of acyclovir; more water soluble (lacks (heptapeptide backbone); large molecule – unable to pass carbonyl group) outer membrane of bacterium  no gram negative activity  Gancyclovir – analogue of acyclovir; prodrug: valganciclovir  Teicoplanin – isolated from Actinoplanes teichumyceticus  Cidofovir – V.B. PLASMA MEMBRANE DISRUPTORS II. AGENTS AGAINST RNA VIRUSES – HIV  Valinomycin & Gramicidin A – ionophores: allows  Nucleotide Reverse Transcriptase Inhibitors (NRTIs) - *3rd uncontrolled movement of ions out of cells letter signifies analogue  Polymycin B – Bacillus polymyxa; causes leakage of small o Zidovudine (AZT) – analogue of deoxythymidine; sugar is molecules such as nucleosides replaced with azido group (N3)  Daptomycin – lipopetide, cyclic; Streptomyces roseosporus o Didanosine (ddI) – analogue of inosine; prodrug: converted to 2’,3’-dideoxyadenosine V.C. PROTEIN SYNTHESIS INHIBITORS o Lamivudine (3TC) & Emtricitabine (FTC) – analogue of cytidine where 3’ carbon is replaced with sulfur  Aminoglycosides o Abacavir – only guanosine analogue NRTI o Streptomycin: Streptomyces griseus o Stavudine (d4T) – thymidine analogue o carbohydrate structures which includes basic amine groups o Zalcitabine (ddC) – cytidine analogue o slightly alkalines – positive charge in basic media  NNRTIs – generally hydrophobic molecules; non-competitive;  Tetracyclines reversible inhibitors o Chlortetracyclines: Streptomyces aureofaciens  gold- o 1st Generation – Nevirapine, Delaviridine colored o 2nd Generation – Efavirenz, Atravirine o four annulated ring  octahydronaphthalene  Chloramphenicol – Streptomyces venezuelae; alcohol and NO2 are important in receptor interaction; dichloroacetamide group is essential for activity; NO2 is responsible for toxicity; contain 2 assymetric centers R,R isomer (active)  Macrolides – Erythromycin – Streptomyces erythreus PAGE 5 OF 7 © MANOR REVIEW CENTER NOTES (K.L) III. OTHER ANTICANCER DRUGS  Nizatidine – equipotent with ranitidie; furan ring is replaced  Antimetabolites with thiazole o Dihydrofolate Reductase Inhibitors (DHFR) – maintains levels of tetrahydrofolic acid (FH4) VIII. PROTON PUMP INHIBITORS (PPIs)  Methotrexate – similar in structure with folates with  substituted benzamidazole additional methyl and amino groups  Prodrug – converted to sulfonamide in acid media  forms a o Thymidilate Synthase Inhibitors disulfide bond with H+/K+ ATPase (proton pump)  5-Fluorouracil – converted to fluorinated analogue of 2’- deoxyuridulic acid monophosphate o DNA Polymerase Inhivitors IX. HYPOGYLCEMIC AGENTS  Cytarabine – analogue of 2-deoxy-cytidine I. INSULIN  Gemcitabine – prodrug of cytarabine with fewer side  produced from B-cells of pancreas effects o Precursor: proinsulin (86 amino acid precursor)  o Purine Antagonist proteolytic cleavage of proinsulin results to insulin + C-  6-Mercaptopurine – falsely incorporated to DNA or RNA peptide o Insulin Molecule – consists of 2 chains (disulfide linkages): VII. ANTIHISTAMINES  Chain A – 21 amino acids  Chain B – 31 amino acids I. STRUCTURE OF HISTAMINE  Rapid-Acting Insulin  Composed of an imidazole ring + ethylamine chain; precursor: o Insulin Lispro – lysine and proline are interchanged in histidine; enzyme histidine decarboxylase position 28 and 29 of B chain; first monomeric analog marketed; stabilized by cresol preservative into hexamers; II. H1 ANTAGONIST drug dissociates to monomers upon SC o Insulin Aspart – replacement of proline with aspartic acid at position 28 of B chain X – connecting atom o Insulin Glulisine – glutamic acid replaces lysine B29 and lysine replaces asparagine at B3  Short-Acting Insulin o Regular Insulin – soluble zinc insulin; only insulin  Basis of Classification administered IV o First Generation – sedating  Intermediate-Acting  Ethanolamines – X: CHO connecting moiety; N,N – o Neutral Protamine Hagedorn (NPH)/Isophane Insulin – dimethyl ethanolamine; (ex. Diphenhydramine; suspension of insulin in a complex with zinc and protamine Dimenhydrinate-8-chlorotheophyllinate – salt of in phosphate buffer diphenhydramine; Doxylamine) o Lente Insulin/Insulin Zn Suspension – mixture of crystallized  Ethylenediamines – X: N atom; (ex. Pyrilamine) insulin (Ultralente) and amorphous (Semilente) insulin in  Piperazines – acylic ethylenediamines; X: CHN group; (ex. acetate buffer Cyclizine; Meclizine)  Long-Acting Insulin  Propylamines – X: carbon atom; (ex. Chlorphheniramine; Brompheniramine) o Insulin Glargine – asparagine at B21 is replaced by glycine o Insulin Detemir – myristic acid is bound to lysine residue at  Phenothiazines – antipsychotic effect; X: sulfur; (ex. B29 Promethazine) o Second Generation II. SULFONYLUREAS  Loratadine  Cetirizine – acid metabolized of hydroxyzine  urea derivative with arylsulfonyl group at position 1 and aliphatic group at position 3 III. H2 ANTAGONISTS – lead compound: guanylhistamine o R’ – influences duration of action o R” – aliphatic; 3-6 carbons  Cimetidine (Tagamet®) – cyanoguanidine analogue; enzyme inhibitor  First Generation – Tolbutamide; Chlorpropramide  Ranitidine (Zantac®) – imidazole is replaced with furan; fewer  Second Generation – Glipizide; Glyburide side effects; longer duration of action; 10x more potent than cimetidine III. BISGUANIDES  Famotidine – imidazole is replaced with guanidinothiazole  Contains bisguanide in which 2 guanidines are linked together; moiety; 30x more potent than cimetidine (ex. Metformin) PAGE 6 OF 7 © MANOR REVIEW CENTER NOTES (K.L) X. CNS DRUGS  Fenamates – N-aryl anthrnilic  intravenous aesthetics COOH anthranilic acid  Benzodiazepines (-zepams) – anxiolytic; sedative; hypnotic effects; substituent at 5th position must be electronegative (confer sedative, hypnotic effect) NH2  Barbiturates – weak acids  Oxicams – 4-hydroxybenzothiazine heterocycle; higher COX-2 o nucleus: barbituric acid selectivity substitution on 5th position confers sedative effect   COX-2 Selective – “-coxibs”; diaryl-5-membered heterocyclic disubstituted barbituric acid; containing a polar sulfonamide group; sulfonamide binds to a o classification: based on DOA group in COX-2 which is not present in COX-1 ↑ lipid/water partition coefficient  shorter duration of action  Anilines & p-Aminophenols  Etomidate – substituted imidazole OH  Propofol – phenolic; formulated as emulsion (not water soluble)  Ketamine – relative of phencyclidine; produces a sense of dissociation from events  dissociative anesthesia (“cataleptic anesthesia”)  Antipsychotics  Antidepressants NH 2  Local Anesthetics o Coal Tar Analgesics – aniline and acetanilide; toxic side o Lipophilic Aromatic Portion effects: methemoglobinemia o Hydrophilic Amino Portion o p-Aminophenol Derivatives – safer; Acetaminophen o Intermediate Chain  Esters – aromatic acid + amino alcohol  Amides – aromatic amino + amino acid XI. ANALGESICS I. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)  General SAR – molecule must have an ionizable acid groups and aromatic system; a second non co-planar ring increases potency; S-isomers are more potent  Salicylic Acid Derivatives o Salicylic Acid  Acetylsalycilic Acid o Diflunisal – difluorophenyl analogue of salicylic acid  Propionic Acid Derivatives o Examples: Ibuprofen; Naproxen; Ketoprofen; Nabumetone – prodrug which contains non-acidic ketones  Arylacetic Acid Derivatives – activity lies on S-isomer o Indole Acetic Acid – Sulindac; Indomethacin; Etodolac o Pyrrole Acetic Acid – Ketorolac PAGE 7 OF 7 © MANOR REVIEW CENTER NOTES (K.L)