LONG-ACTING DIHYDROPYRIDINE CALCIUM-ANTAGONISTS .1. 2-ALKOXYMETHYL DERIVATIVES INCORPORATING BASIC SUBSTITUENTS
LONG-ACTING DIHYDROPYRIDINE CALCIUM-ANTAGONISTS .1. 2-ALKOXYMETHYL DERIVATIVES INCORPORATING BASIC SUBSTITUENTS
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DOI：
10.1021/jm00159a022
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发表时间：
1986-09-01
影响因子：
7.3
通讯作者：
BLACKBURN, KJ
中科院分区：
文献类型：
--
作者：
ARROWSMITH, JE;CAMPBELL, SF;BLACKBURN, KJ
描述了一系列在2-位被碱性侧链取代的二氢吡啶类化合物，并列出了它们作为钙拮抗剂的效力。发现一种化合物2-[（2-氨基乙氧基）甲基]-4-（2-氯苯基）-3-乙氧羰基-5-甲氧羰基-6-甲基-1，4-二氢吡啶（17，N）的效力与硝苯地平相当，在狗体内的消除半衰期为30小时。口服生物利用度接近100%，血流动力学反应是逐渐开始和持久的影响。已经制备了两种对映异构体，发现大部分活性存在于（-）异构体18中。对17的类似物进行的X射线晶体学研究表明，侧链氧和环氮上的质子之间存在弱氢键。
A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting effect. The two enantiomers have been prepared and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.