Synthesis and calcium channel antagonist activity of 1,4-dihydropyridine derivatives containing 4-nitroimidazolyl substituents.

Alkyl, cycloalkyl and arylakyl ester analogues of nifedipine (CAS 21829-25-4), in which the ortho-nitro phenyl group at position 4 is replaced by 1-methyl-4-nitro-5-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 in C-3 and C-5 ester substituents for more than two methylene units (n > 1) decreases activity. In the phenylalkyl ester series increasing the length of methylene chain increases activity. In the series of unsymmetrical phenylalkyl esters (R2 = Me or Et) increasing the length of the methylene chain decreases activity. The results demonstrate that most of the compounds had similar activity to the reference drug nifedipine. Among symmetrical diesters (methyl, ethyl and phenylpropyl derivatives) and among unsymmetrical series (benzyl methyl, benzyl ethyl and phenethyl ethyl derivatives) were more active than the reference drug nifedipine. The unsymmetrical phenethyl ethyl derivative was the most potent antagonist tested. The structure-activity data indicate that the 4-(1-methyl-4-nitro-5-imidazolyl) moiety, bioisoester of 2-nitro-phenyl moiety, is as good as other nitro-imidazolyl moieties.