Synthesis and Calcium Channel Modulating Effects of Alkyl 1,4‐Dihydro‐2,6‐dimethyl‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐(1H‐tetrazol‐5‐yl)‐3‐pyridinecarboxylates

Abstract

AbstractA group of racemic alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐(1H‐tetrazol‐5‐yl)‐3‐pyridinecarboxylates 11–14 were prepared using the Hantzsch reaction that involved the condensation of 2‐, 3‐ or 4‐pyridinecarboxaldehyde, or 2‐trifluoromethylbenzaldehyde, 8a–d with isopropyl or methyl 3‐aminocrotonate (9a–b) and 5‐(2‐oxopropyl)‐1H‐tetrazole (10a) or 5‐(2‐oxopropyl)‐1‐methyl‐1H‐tetrazole (10b). In vitro calcium channel (CC) antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. In the series of compounds 11–14, only compounds 14a and 14b exhibited some weak CC antagonist activity (10−6 M range) relative to the reference drug nifedipine (IC50 = 1.43 × 10−8 M). Compounds 11b‐14b having a 1‐methyl‐1H‐tetrazol‐5‐yl substituent were inactive CC agonists on GPLA. In contrast, compounds 12a‐14a having a 1H‐tetrazol‐5‐yl substituent exhibited CC agonist activity on GPLA, but the C‐4 2‐pyridinyl analog 11a exhibited a mild negative inotropic effect. The approximately equipotent CC agonist activity (GPLA) exhibited by the C‐4 pyridinyl 13a and 4‐(2‐trifluoromethylphenyl) 14a compounds compared favorably with that of the reference drug (±)‐Bay K 8644 (EC50 = 7.7 × 10−7 M) indicating that the 1H‐tetrazol‐5‐yl moiety is a suitable replacement for the nitro group present in Bay K 8644 with respect to cardiac CC agonist activity. These latter compounds 13a and 14a should serve as useful probes to study the structure‐function relationships of calcium channels.