Medicinal Chemistry of Select Cardiovascular Drugs PDF

Medicinal Chemistry of Select Cardiovascular Drugs Decoding Structure-Activity Relationships Mr Sean Alcorn ACEi & ARBs ACE inhibitors • ACE is a zinc metallopeptidase • The most important structurefunction relationship of ACEinhibitors is their ability to interact with that zinc component, i.e....

Medicinal Chemistry of Select Cardiovascular Drugs Decoding Structure-Activity Relationships Mr Sean Alcorn ACEi & ARBs ACE inhibitors • ACE is a zinc metallopeptidase • The most important structurefunction relationship of ACEinhibitors is their ability to interact with that zinc component, i.e. the zincbinding moiety of the drug molecule ACE binding model Carboxylate binds to Arg Binds Zn2+ + Zn2 Binding • Sulfhydryl (-SH) group: • captopril • dicarboxylate (-COOH) group: • enalapril, • lisinopril • perindopril • quinapril • ramipril • phosphoryl (-PO2) group: • fosinopril groups AT2 antagonists • Are mimics of the AT2 amino acid sequence • Their specificity for docking with the AT1 receptor is a couple of salt bridges between side-chains which bind to the receptor site but do not activate the actual receptor. • Angiotensin II binds via both these salt bridges as well as at a couple of other binding sites, which is what confers the activating effect. Calcium Channel Blockers Classification 1,4 Dihydropyridines • • • • • amlodipine felodipine nifedipine lercanidipine etc. BP Non-dihydropyridines • Diphenyl alkylamines • verapamil • Benzothiazepine derivatives • diltiazem HR Dihydropyridines Dihydropyridines Aromatic ring substitution Aromatic ring substitution Verapamil Diltiazem Beta-blockers Aryloxypropanolamine backbone Aryl oxy propanolamine propranolol sotalol metoprolol atenolol Substituents on the Aryl Ring Selectivity is determined whether the side-chain of the aryl ring is in the -para, -meta or -ortho position propranolol metoprolol atenolol bisoprolol Para-substitution Lipid solubility propranolol better GI absorption (eg. the absorption of atenolol is usually incomplete, only 50%) atenolol a shorter plasma half-life (mainly due to rapid distribution) Greater protein binding (which means less predictable pharmacokinetics during critical illness) higher tissue penetration (eg. the most lipid-soluble beta-blocker is propanolol, which means it penetrates the blood-brain barrier most readily. Non-selective alpha/beta blockers Prazosin