title: Synthesis and calcium channel antagonist activity of alkyl cycloalkyl esters of nifedipine containing pyridinyl substituents.
abstract: Alkyl cycloalkyl esters of nifedipine (1a) analogues, in which the ortho-nitrophenyl group at position 4 is replaced by pyridinyl (5-19) were synthesized and evaluated as calcium channel antagonists using the muscarinic receptor-mediated Ca(2+)-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activity profile for unsymmetrical esters (5-15), which indicated the effect of cycloalkyl ring size on activity, was cyclopentyl > cyclohexyl > cyclobutyl. In addition unsymmetrical esters, possessing one R2-cyclohexyl substituent, exhibited an activity profile dependent upon the nature of the R1-alkyl ester substituent with Me > Et, i-Pr, i-Bu > cyclohexyl > t-Bu. The point of attachment of the C-4 pyridinyl substituent was also a determinant of activity for unsymmetrical compounds (R1 = Me, i-Pr; R2 = cyclohexyl, cyclobutyl) where the relative potency order was 2-pyridinyl > 3-pyridinyl > 4-pyridinyl. In contrast, when the R1 and R2-substituents are larger in size (R1 = R2 = cyclohexyl or R1 = i-Pr, R2 = cyclopentyl) the relative activity profile was 3-pyridinyl = 4-pyridinyl > 2-pyridinyl. The C-3 and C-5 ester substituents therefore appear to provide important interdependent contributions to calcium channel antagonist activity, and hence to interaction with the 1,4-dihydropyridine receptor site.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: M R
authors.initials: MR
authors.lastname: Akula
authors.forename: W C
authors.initials: WC
authors.lastname: Matowe
authors.forename: M W
authors.initials: MW
authors.lastname: Wolowyk
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D011725:Pyridines; D009543:Nifedipine