DIHYDROPYRIMIDINE CALCIUM-CHANNEL BLOCKERS .3. 3-CARBAMOYL-4-ARYL-1,2,3,4-TETRAHYDRO-6-METHYL-5-PYRIMIDINECARBOXYLIC ACID-ESTERS AS ORALLY EFFECTIVE ANTIHYPERTENSIVE AGENTS

被引:893
作者
ATWAL, KS
SWANSON, BN
UNGER, SE
FLOYD, DM
MORELAND, S
HEDBERG, A
OREILLY, BC
机构
[1] Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000
关键词
D O I
10.1021/jm00106a048
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In order to explain the potent antihypertensive activity of the modestly active (IC50 = 3.2-mu-M) 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.
引用
收藏
页码:806 / 811
页数:6
相关论文
共 10 条