Long-acting dihydropyridine calcium antagonists. 3. Synthesis and structure-activity relationships for a series of 2-[(heterocyclylmethoxy) methyl]derivatives

Article abstract of DOI:10.1021/jm00130a026

The preparation of 1,4-dihydropyridines containing (heterocyclylmethoxy)methyl groups in the 2-position is described and the structural identification of certain of the compounds using ¹H NMR spectroscopic methods is reported. The calcium antagonist activity of the compounds on rat aorta is listed and is compared with the negative inotropic potency as determined by using a Langendorff-perfused guinea pig heart model. Several compounds are more potent than nifedipine and show greater selectivity for the vasculature over the heart. One compound, 2-[[(2-amino-4-hydroxypyrimidin-6-yl)methoxy]methyl]-4-(2,3- dichlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4- dihydropyridine (27, UK-56,593), was identified as a potent (IC₅₀ = 1.6 x 10^-9 M), tissue-selective calcium antagonist which proved to have a markedly longer duration of action (>4.5 h) than nifedipine in the anesthetized dog on intravenous administration.