Design and syntheses of C‐4 4‐(1‐methoxycarbonyl‐1,2‐dihydropyridyl)‐, and 3‐[1‐methoxycarbonyl‐1,2‐(and 1,6‐)dihydropyridyl]‐, derivatives of alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐5‐pyridinecarboxylates with cardiospecific calcium channel agonist activity

Abstract

A group of hitherto unknown alkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(dihydropyridyl)-5-pyridinecarboxylates possessing 4-[4-(1-methoxycarbonyl-1,2--dihydropyridyl)]- (6-10), or 4-[3-(1-methoxycarbonyl-1,2-(and 1,6-)dihydropyridyl)]- (16-20), moieties were synthesized by reaction of the 4-(4-pyridyl)- (1-5), or 4-(3-pyridyl)- (11-15), precursors with methyl chloroformate in the presence of sodium borohydride. In vitro calcium channel (CC) antagonist activities were determined using a muscarinic-receptor-mediated Ca 2+ -dependent contraction of guinea pig ileal longitudinal smooth muscle (GPILSM) assay. Elaboration of the 4-pyridyl (1-5), or 3-pyridyl (11-16), substituent to the corresponding 1,2-(1,6)dihydropyridyl moiety abolished the CC agonist effect produced by 1-5 and 11-15 on GPILSM. In addition, all alkyl esters possessing a 4-[4- or 3-(1-methoxycarbonyl-1,2--(1,6-)dihydropyridyl)]- moiety (6-10, 17, 19-20) were inactive CC antagonists on GPILSM with the exception of the ethyl (16) and isobutyl (18) ester derivatives, which exhibited weak CC antagonist activity. All of the 4-[4- or 3-(1-methoxycarbonyl-1,2-(1,6-)dihydropyridyl)] compounds evaluated (6-10, 16-19) exhibited in vitro CC agonist (positive inotropes) activity on guinea pig left atria (GPLA). In general, the 4-[3-(1-methoxycarbonyl-1,2-(and 1,6)dihydropyridyl)] compounds (16-19) were more potent CC agonists (EC 50 = 2.91 × 10 -6 to 7.51 x 10 -6 M range) than the corresponding 4-[4-(1-methoxycarbonyl-1,2-dihydropyridyl)] compounds (6-9, EC 50 = 1.42 x 10 -5 to 2.65 x 10 -5 M range). These 4-[4- or 3-(1-methoxycarbonyl-1,2-(1,6)dihydropyridyl)] compounds, which exhibit cardiospecific CC agonist activity (6-10, 17, 19) will serve as valuable model compounds to study the structure-function relationships of CC modulation, and provide a new drug design concept directed toward the treatment of congestive heart failure.