Synthesis and evaluation of pharmacological activities of 3,5-dialkyl 1,4-dihydro-2,6-dimethyl-4-nitroimidazole-3,5-pyridine dicarboxylates

New analogues of nifedipine, in which the 2-nitrophenyl group at position 4 is replaced by a 1-methyl-5-nitro-2-imidazolyl substituent, were synthesized. The symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicarboxylates were prepared by a classical Hantzsch condensation. The asymmetrical analogues were synthesized using a procedure reported by Iwanami that involved the condensation of alkylacetoacetate with methyl-, ethyl- or isopropyl-3-aminocrotonate and 1-methyl-5-nitroimidazole-2-carboxaldehyde. Calcium channel antagonist activities were determined in vitro using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Many compounds exhibited superior, or equipotent, calcium antagonist activity (IC50 = 10(-10) to 10(-13) M range) relative to the reference drug nifedipine (IC50 = 1.09 +/- 0.12 x 10(-11) M). Antinociceptive effects of some compounds were evaluated by the mouse tail-flick assay in vivo. Results demonstrate that some of the compounds were active as an antinociceptive.