Synthesis and smooth muscle calcium channel antagonist effects of dialkyl 1,4-dihydro-2,6-dimethyl-4-aryl-3,5-pyridinedicarboxylates containing a nitrooxy or nitrophenyl moiety in the 3-alkyl ester substituent.
A group of racemic 3-[2-nitrooxyethyl (1,3-dinitrooxy-2-propyl or 4-nitrophenylethyl)] 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-[2- trifluoromethylphenyl (2-nitrophenyl or 3-nitrophenyl)]-3,5-pyridinedicarboxylates 13-15 were prepared using the Hantzsch reaction that involved the condensation of 2-nitrooxyethyl 9a, 1,3-dinitrooxy-2-propyl 9b or 4-nitrophenylethyl 9c acetoacetate with isopropyl 3-aminocrotonate 11 and 2-trifluoromethyl 12a, 2-nitro 12b or 3-nitro 12c benzaldehyde. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 13-15 exhibited superior, or equipotent, calcium channel antagonist activity (10(-8) to 10(-10) M range) relative to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). The R1 C-3 ester substituent was a determinant of calcium channel antagonist activity where the potency order was CH2CH2ONO2 > CH2CH2-C6H4-4-NO2 > or = CH(CH2ONO2)2. In contrast, the C-4 R2-aryl substituent (2-CF3-C6H4-, 2-O2N-C6H4- or 3-O2N-C6H4-) was not a major determinant of activity. Compounds 13a-15a, which possess a 3-(2-nitrooxyethyl) ester substituent exhibit superior calcium channel antagonist smooth muscle relaxant activity (IC50 = 10(-10) M range) relative to nifedipine, could serve as potential probes to investigate the in vivo release of nitric oxide (NO) which induces vascular muscle relaxation.
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
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D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000494:pharmacology*; D004952:Esters / Q000737:chemistry; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009566:Nitrates / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D002264:Carboxylic Acids; D004952:Esters; D009566:Nitrates; D011725:Pyridines