DIHYDROPYRIMIDINE CALCIUM-CHANNEL BLOCKERS - 2-HETEROSUBSTITUTED 4-ARYL-1,4-DIHYDRO-6-METHYL-5-PYRIMIDINECARBOXYLIC ACID-ESTERS AS POTENT MIMICS OF DIHYDROPYRIDINES

2-Heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters 8, which lack the potential Cs symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers. © 1990, American Chemical Society. All rights reserved.