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 (IC 50 = 1.43 × 10 −8 M). The R 1 C‐3 ester substituent was a determinant of calcium channel antagonist activity where the potency order was CH 2 CH 2 ONO 2 > CH 2 CH 2 ‐C 6 H 4 ‐4‐NO 2 ≥ CH(CH 2 ONO 2 ) 2 . In contrast, the C‐4 R 2 ‐aryl substituent (2‐CF 3 ‐C 6 H 4 ‐, 2‐O 2 N‐C 6 H 4 ‐ or 3‐O 2 N‐C 6 H 4 ‐) 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 (IC 50 = 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.