Atwal K S, Rovnyak G C, Kimball S D, Floyd D M, Moreland S, Swanson B N, Gougoutas J Z, Schwartz J, Smillie K M, Malley M F
Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
J Med Chem. 1990 Sep;33(9):2629-35. doi: 10.1021/jm00171a044.
To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.
为提高二氢嘧啶类钙通道阻滞剂的内在活性，我们将先前描述的2-杂烷基-1,4-二氢嘧啶的结构修饰为3-取代的1,4-二氢嘧啶。使用钾去极化兔主动脉进行的构效关系研究表明，邻位、间位二取代芳基衍生物比邻位或间位单取代化合物更具活性。虽然血管舒张活性严重依赖于C5酯基的大小，其中异丙酯最佳，但N3位可耐受多种取代基（氨基甲酸酯、酰基、磺酰基、烷基）。我们的结果表明，二氢嘧啶3比相应的2-杂烷基-1,4-二氢嘧啶2活性显著更高，且仅比类似取代的2-杂烷基-1,4-二氢吡啶4和5活性略低。虽然二氢吡啶对映体的活性通常有10-15倍的差异，但二氢嘧啶3j的对映体活性差异超过1000倍。这些结果强化了烯胺酯与二氢吡啶受体结合的必要性，并表明N3取代基具有非特异性作用。
