Abstract
Alkyl, cycloalkyl or aryl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 1-methyl-5-nitro-2-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylene chain (n > 2) decreases activity. The relative activity profile for asymmetrical esters was cyclopentyl > cyclohexyl > cyclopropyl. Comparison of esters having the same methylene space showed that the cyclohexyl compounds were more active than the corresponding phenyl derivatives. In addition, asymmetrical esters possessing one R2 substituent (methyl > ethyl) indicated that increasing the length of methylene chain in the R1-substituent decreased activity. Our results demonstrate that several compounds were more active than the reference drug nifedipine. The symmetrical cyclohexyl ester (n = 0) and the asymmetrical (R1 = cyclohexyl, R2 = Me, n = 0) derivatives were the most potent antagonists tested.
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