Synthesis and calcium channel antagonist activity of alkyl t-butyl esters of nifedipine analogues containing pyridinyl substituents

Abstract

Alkyl t-butyl esters of Nifedipine (1a) analogues, in which the o-nitrophenyl group at position 4 is replaced by pyridinyl (7), dihydropyridinyl (8-10), or N-methyltetrahydropyridinyl (12), 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 pyridinyl esters (7a-c) was 2-pyridinyl greater than 3-pyridinyl greater than 4-pyridinyl, whereas for the symmetrical di-tert-butyl esters (7d-f) the order of activity was 3-pyridinyl greater than 4-pyridinyl greater than 2-pyridinyl. Compounds (7a-c) having non-identical ester substituents were more active than those possessing identical ester substituents (7d-f). The 4-(3-pyridinyl) compounds (7) were more active than the 4-[3-(dihydropyridinyl)] regioisomers (8-9) whereas the 4-[4-(dihydropyridinyl)] compounds (10) were more active than the 4-(4-pyridinyl) analogues (7). The 4-[3-(dihydropyridinyl)] analogues (8-9) were more active than their respective 4-(4-dihydropyridinyl)] analogues (10). Compounds (12) having a 4-(1-methyl-1,2,3,6-tetrahydropyridinyl) ring substituent exhibited low activity. The test results suggest that that 4-(pyridinyl) and 4-(dihydropyridinyl) are isosteric with 4-(nitrophenyl) when they substitute on a 1,4-dihydropyridine ring system, 2-, 3- and 4-nitrophenyl being isosteric with 2-, 3- and 4-pyridinyl and dihydropyridinyl, respectively.