Synthesis and calcium channel antagonist activities of 3-nitrooxyalkyl, 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3, 5-pyridinedicarboxylates

A group of racemic 3-[(2-nitrooxyethyl), (3-nitrooxypropyl), (4-nitrooxybutyl) or (1,3-dinitrooxy-2-propyl)], 5-methyl (ethyl or propyl) 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicarboxylates (18-29) were synthesized using modified Hantzsch reaction that involved the condensation of 2-nitrooxyethyl (8), 3-nitrooxypropyl (9), 4-nitrooxybutyl (10) or 1,3-dinitrooxy-2-propyl (13) acetoacetate with methyl (14), ethyl (15) or isopropyl (16) 3-aminocrotonate and 1-methyl-5-nitroimidazole-2-carboxaldehyde (17). In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 18-29 exhibited superior, or equipotent, calcium antagonist activity (IC50= 10(11) - 10(-13) M range) relative to the reference drug nifedipine (IC50 = 1.07 +/- 0.12 x 10(-11) M), which could serve as potential probes to investigate the in vivo release of nitric oxide which induces vascular muscle relaxation.