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

• Published in: Farmaco (Società chimica italiana : 1989) Vol. 57; no. 2; pp. 123 - 128
• Main Authors: Miri, Ramin, Niknahad, H, Vesal, Gh, Shafiee, A
• Format: Journal Article
• Language: English
• Published: France Elsevier SAS 01-02-2002
• Subjects: Animals; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - pharmacology; Calcium channels; Calcium Channels - metabolism; Dihydropyridine; Guinea Pigs; Ileum - drug effects; Inhibitory Concentration 50; Male; Molecular Structure; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Nitroimidazole; Nitrooxyalkyl; Organ Culture Techniques; Organic nitrate; Pyridines - chemical synthesis; Pyridines - pharmacology; Structure-Activity Relationship; Calcium channels; Dihydropyridine; Nitrooxyalkyl; Nitroimidazole; Organic nitrate
• ISSN: 0014-827X; 1879-0569
• DOI: 10.1016/S0014-827X(01)01183-1

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 (IC
50=10
−11–10
−13 M range) relative to the reference drug nifedipine (IC
50=1.07±0.12×10
−11 M), which could serve as potential probes to investigate the in vivo release of nitric oxide which induces vascular muscle relaxation.