Molecular Modification in Drug Design Flashcards
Drug Development Cycle
target validation and lead selection pre-clinical (lead) phase 1 phase 2 phase 3 submission
Lead compound discovery
- natural product research
- chemical alteration of known substrates and metabolites
- random screening of chemical libraries
- de novo synthesis of compounds designed to interact with a biological target
- structural optimization of specific adverse effect that is beneficial in the treatment of another disease
Conformational Restriction: phenothiazine antipsychotics
-d2 receptor antagonists
EX: chlorpromazine active conformation requires that aliphatic amine lies on same side as chlorine containing aromatic ring
—-> Z-isomers potency > E-isomers potency
Variation of Functional Groups - Steroids
testosterone: rapidly oxidized (c17: COH –> CO)
ethinyl estradiol: orally available (CCH–> CH3)
Variation of Functional Groups: Angiotensin 2 receptor blockers (ARBs)
substituite COOH with similarly acidic tetrazole to provide physicochemical and pharmacological advantages
–> tetrazole is less likely to undergo metabolism, more lipophilic, enhances oral absorption and better charge distribution
Variation of Functional Groups- Sulfonylurea Class of Antidiabetic Agents
-para methyl substituent undergoes rapid benzylic oxidation to an inactive COOH metabolite; cholera group produces significant change in DOA
Lincosamide antibiotics
- replacement of hydroxyl group with chloro group enhances lipophilic character
- -> clindamycin = improved absorption after oral administration
Variation of Functional Groups: Zidovudine; conversion of substrate to an inhibitor
- anti-human immunodeficiency virus infections (HIV)
- mechanism of DNA and RNA polymerase and enzymes ; 3’-OH and 5’-triphosphate are required
- 3’ hydroxyl group has been replaced with a 3’ azido group
Variation: Sulfonamides, anti-metabolite
-PABA contains primary aromatic amine and an ionizable COOH that are located para to one another
Erlenmeyer isosteres
- N,NH,NH2: basic amines capable of undergoing ionization at physiological pH
- CH,CH2,CH3,O,OH,SH and halogens: neutral functional group that will not be ionized at pH 7.4
- N,NH,NH2,and OH: enhance water solubility
- C,CH,CH2,CH3 and halogens: enhance lipid solubility
- *important that difference are considered when evaluating relative activities of isometric compounds**
CH915 example replacements
- isotere A: addition of primary amine will allow for additional ionic binding with target and may affect pKa of secondary amine
- isotere B: substitution of CH3 for OH will enhance lipid solubility; less H binding
- isotere C: replacement of secondary amine with ether may prevent ionic binding with target
Classical Bioisosteric replacements
- cholrpropamide and tolbutamide: decreased metabolism and longer DOA
- lincomycin and clindamycin: improved F and enhanced bacterial penetration
- anti-arryhthmic
- AMP and GMP
- 6-mercaptopurine: anti-metabolite
- acetazolamide
- rapid ester hydrolysis; confers poor F and relatively short DOA
- key intermediate in biosynthesis of AMP and GMP
- T-IMP competitively inhibits conversion of IMP to AMP and GMP; useful in treatment of acute lymphoblastic leukemia
- acetazolamide: inhibitors of carbonic anhydrase; unsubstituted sulfonamide group is isometric with carbonic acid
Homologation: separation of B1 and B2 activity
metaproterenol and terbutaline: b1 receptor requires a catechol ring, wbut hulk N-sub. is allowed for B2 activity and decreases B1 receptor interaction; similar to epi
Homologation: conversion of an agonist to an antagonist
EX: morphine; homologation of the methyl group produces a compound that acts as an opioid u receptor antagonist
