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.
Miri
Ramin
R
Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Science, Iran. mirir@sums.ac.ir
Niknahad
H
H
Vesal
Gh
G
Shafiee
A
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009924:Organ Culture Techniques; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011725:Pyridines