Long-acting dihydropyridine calcium antagonists. 5. Synthesis and structure-activity relationships for a series of 2-[[(N-substituted-heterocyclyl)ethoxy]methyl]-1,4-dihydropyridine calcium antagonists

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Abstract
The synthesis of a series of 1,4-dihydropyridines which have N-linked heterocycles at the terminus of an ethoxymethyl chain at the 2-position is described. The calcium antagonist activity on rat aorta of this class of DHPs is compared with their negative inotropic activity as determined by using a Langendorff-perfused guinea pig heart mode. The compounds examined show a wide range of selectively for vascular over cardiac tissue, with those analogues which possess an amide group at the terminus of the 2-substitutent proving the most selective. From the in vitro data obtained for a series of 1,2,3-triazoles, it is possible to conclude that the SARs for binding to the calcium channels in vascular and cardiac tissue are different. One of the compounds, 2-amino-1-[2-[[4-(2,3-dichlorophenyl)-3-(ethyoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl]methoxy]ethyl]4(3H)-imidazolone (20b, UK-55,444), was identified as a potent (IC50 = 8 .times. 10-9 M) calcium antagonist which is 40-fold selective for vascular over cardiac tissue and which has a significantly longer duration of action (> 3 h) than nifedipine in the anesthetized dog on intravenous administration.

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