Atwal K S, Swanson B N, Unger S E, Floyd D M, Moreland S, Hedberg A, O'Reilly B C
Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
J Med Chem. 1991 Feb;34(2):806-11. doi: 10.1021/jm00106a048.
In order to explain the potent antihypertensive activity of the modestly active (IC50 = 3.2 microM) dihydropyrimidine calcium channel blocker 5, we carried out drug metabolism studies in the rat and found 5 is metabolized to compounds 6-10. Two of the metabolites, 6 (IC50 = 16 nM) and 7 (IC50 = 12 nM), were found to be responsible for the antihypertensive activity of compound 5. Potential metabolism of 6 into 7 in vivo precluded our interest in pursuing compounds related to 6. Structure-activity studies aimed at identifying additional aryl-substituted analogues of 7 led to 17g,j,p with comparable potential in vivo, though these compounds were less potent than 7 in vitro. To investigate the effects of absolute stereochemistry on potency, we resolved 7 via diastereomeric ureas 19a,b, prepared from 18 by treatment with (R)-alpha-methylbenzylamine. Our results demonstrate that the active R-(-)-enantiomer 20a of 7 is both more potent and longer acting than nifedipine (1) as an antihypertensive agent in the SHR. The in vivo potency and duration of 20a is comparable to the long-acting dihydropyridine amlodipine. The superior oral antihypertensive activity of 20a compared to that of previously described carbamates 2 (R2 = COOEt) could be explained by its improved oral bioavailability, possibly resulting from increased stability of the urea functionality.
为了解释活性适中（IC50 = 3.2 microM）的二氢嘧啶钙通道阻滞剂5具有强大的降压活性的原因，我们在大鼠身上进行了药物代谢研究，发现5代谢为化合物6 - 10。其中两种代谢产物，6（IC50 = 16 nM）和7（IC50 = 12 nM），被发现是化合物5降压活性的原因。6在体内可能代谢为7，这使我们不再对与6相关的化合物进行研究。旨在鉴定7的其他芳基取代类似物的构效关系研究得到了在体内具有相当潜力的17g、j、p，尽管这些化合物在体外的活性不如7。为了研究绝对立体化学对活性的影响，我们通过由18与（R）-α-甲基苄胺反应制备的非对映体脲19a、b拆分了7。我们的结果表明，7的活性R - (-)-对映体20a作为SHR中的降压剂，比硝苯地平（1）更有效且作用时间更长。20a的体内活性和持续时间与长效二氢吡啶氨氯地平相当。与先前描述的氨基甲酸酯2（R2 = COOEt）相比，20a具有更高的口服降压活性，这可能是由于其口服生物利用度提高，可能是由于脲官能团的稳定性增加所致。
