Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists. 3. Discovery of a Potent, 2-Nonaryl, Highly Selective ET<sub>A</sub> Antagonist (A-216546)
作者:Gang Liu、Kenneth J. Henry,、Bruce G. Szczepankiewicz、Martin Winn、Natasha S. Kozmina、Steven A. Boyd、James Wasicak、Thomas W. von Geldern、Jinshyun R. Wu-Wong、William J. Chiou、Douglas B. Dixon、Bach Nguyen、Kennan C. Marsh、Terry J. Opgenorth
DOI:10.1021/jm980217s
日期:1998.8.1
was replaced by an n-pentyl group, the resultant antagonist 3 exhibited substantially increased ETB/ETA activity ratio, but a decreased ETA affinity. Structure-activity studies revealed that substitution and geometry of this alkyl group, and substitution on the benzodioxolyl ring, are important in optimizing this series of highly ETA selective antagonists. In particular, the combination of a (E)-2,2-dimethyl-3-pentenyl
以前,我们已经报道了ABT-627(1,A-147627,A-127722的活性对映体)的发现,这是一种基于2,4-二芳基取代的吡咯烷-3-羧酸的内皮素受体A拮抗剂。该化合物以0. 034 nM的亲和力(Ki)结合ETA受体,并且对ETA受体的选择性是ETB受体的2000倍。为了进一步提高ETA选择性,我们在本系列文章中扩展了结构活性研究。当1的对-茴香基基团被正戊基基团取代时,所得拮抗剂3表现出显着提高的ETB / ETA活性比,但降低的ETA亲和力。结构活性研究表明,该烷基的取代和几何形状以及在苯并二氧戊环上的取代对于优化这一系列高度ETA选择性拮抗剂很重要。特别地,(E)-2,2-二甲基-3-戊烯基和7-甲氧基-1,3-苯并二恶唑-5-基的组合提供了对人ETA受体亚型具有亚纳摩尔亲和力的疏水化合物10b。 ETB / ETA活性比超过130000。同时,在合成烯烃化合物的过程中,发现