Atwal K S, Rovnyak G C, Schwartz J, Moreland S, Hedberg A, Gougoutas J Z, Malley M F, Floyd D M
Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
J Med Chem. 1990 May;33(5):1510-5. doi: 10.1021/jm00167a035.
2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic 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.
制备了缺乏二氢吡啶类钙通道阻滞剂潜在CS对称性的2-杂取代-4-芳基-1,4-二氢-6-甲基-5-嘧啶羧酸酯8，并对其生物活性进行了评估。使用钾去极化兔主动脉和放射性配体结合技术进行的生物测定表明，其中一些化合物是二氢吡啶类钙通道阻滞剂的有效模拟物。发现支链酯（如异丙基、仲丁基）和烷硫基（如SMe）的组合对生物活性最为理想。当与类似取代的2-杂烷基二氢吡啶9直接比较时，发现二氢嘧啶8的活性低30倍。二氢嘧啶类似物8g的固态结构表明，这些化合物可以采用与报道的二氢吡啶类钙通道阻滞剂构象相似的分子构象。
