Synthesis, study of 3D structures, and pharmacological activities of lipophilic nitroimidazolyl-1,4-dihydropyridines as calcium channel antagonist.

摘要

QSAR studies indicated that the potency of nifedipine analogues was dependent upon lipophilicity, an electronic term and separated terms for each position on the DHP ring. Changes in the substitution pattern at the C(3), C(4), and C(5) positions of DHPs alter potency, tissue selectivity, and the conformation of the 1,4-DHP ring. In this project a group of alkyl ester analogues of new derivatives of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by a 1-methyl-5-nitro-2-imidazolyl substituent, and the methyl group at position 6 is replaced by a phenyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K(+) contraction of guinea-pig ileal longitudinal smooth muscle. The results for asymmetrical esters showed that lengthening of the substituent in C(3) ester substituent increased activity. When increasing of the length is accompanied by increasing the hindrance, the activity decreased. The results demonstrate that all compounds were more active or similar in effect to that of the reference drug nifedipine.