Design and syntheses of C-4 4-(1-methoxycarbonyl-1,2-dihydropyridyl)-, and3-[1-methoxycarbonyl-1,2-(and 1,6-)dihydropyridyl]-, derivatives of alkyl 1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridinecarboxylates with cardiospecificcalcium channel agonist activity

A group of hitherto unknown alkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(dihyd ropyridyl)- 5-pyridinecarboxylates possessing 4-[4-(1-methoxycarbonyl-1,2-d ihydropyridyl)]- (6-10), or 4-[3-(1-methoxycarbonyl-1,2-(and 1,6-)dihydropy ridyl)]- (16-20), moieties were synthesized by reaction of the 4-(4-pyridyl )- (1-5), or 4-(3-pyridyl)- (11-15), precursors with methyl chloroformate i n the presence of sodium borohydride. In vitro calcium channel (CC) antagon ist activities were determined using a muscarinic-receptor-mediated Ca2+-de pendent contraction of guinea pig ileal longitudinal smooth muscle (GPILSM) assay. Elaboration of the 4-pyridyl (1-5), or 3-pyridyl (11-16), substitue nt to the corresponding 1,2-(1,6)dihydropyridyl moiety abolished the CC ago nist effect produced by 1-5 and 11-15 on GPILSM. In addition, all alkyl est ers 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 ex ception of the ethyl (16) and isobutyl (18) ester derivatives, which exhibi ted weak CC antagonist activity. All of the 4-[4- or 3-(1methoxycarbonyl-1, 2-(1,6-)dihydropyridyl)] compounds evaluated (6-10, 16-19) exhibited in vit ro CC agonist (positive inotropes) activity on guinea pig left atria (GPLA) . In general, the 4-[3-(1-methoxycarbonyl-1,2-(and 1,6)dihydropyridyl)] com pounds (16-19) were more potent CC agonists (EC50 = 2.91 X 10(-6) to 7.51 x 10(-6) M range) than the corresponding 4-[4-(1-methoxycarbonyl-1,2-dihydro pyridyl)] compounds (6-9, EC50 = 1.42 x 10(-5) to 2.65 x 10(-5) M range). T hese 4-[4- or 3-(1-methoxycarbonyl-1,2(1,6)dihydropyridyl)] compounds, whic h exhibit cardiospecific CC agonist activity (6-10, 17, 19) will serve as v aluable model compounds to study the structure-function relationships of CC modulation, and provide a new drug design concept directed toward the trea tment of congestive heart failure. (C) 2000 Wiley-Liss, Inc.