Liu G, Henry K J, Szczepankiewicz B G, Winn M, Kozmina N S, Boyd S A, Wasicak J, von Geldern T W, Wu-Wong J R, Chiou W J, Dixon D B, Nguyen B, Marsh K C, Opgenorth T J
Metabolic Disease Research, Cancer Research, and Drug Analysis Department, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
J Med Chem. 1998 Aug 13;41(17):3261-75. doi: 10.1021/jm980217s.
Previously we have reported the discovery of ABT-627 (1, A-147627, active enantiomer of A-127722), a 2,4-diaryl substituted pyrrolidine-3-carboxylic acid based endothelin receptor-A antagonist. This compound binds to the ETA receptor with an affinity (Ki) of 0. 034 nM and with a 2000-fold selectivity for the ETA receptor versus the ETB receptor. We have expanded our structure-activity studies in this series, in an attempt to further increase the ETA selectivity. When the p-anisyl group of 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 group and a 7-methoxy-1,3-benzodioxol-5-yl group provided hydrophobic compound 10b with subnanomolar affinity for human ETA receptor subtype and with an ETB/ETA activity ratio of over 130000. Meanwhile, synthetic efforts en route to olefinic compounds led to the discovery that 2-pyridylethyl (9o) and 2-(2-oxopyrrolidinyl)ethyl (9u) replacement of the p-anisyl group of 1yielded very hydrophilic ETA antagonists with potency and selectivity equal to those of 10b. On the basis of overall superior affinity, high selectivity for the ETA receptor (Ki, 0.46 nM for ETA and 13000 nM for ETB), and good oral bioavailability (48% in rats), A-216546 (10a) was selected as a potential clinical backup for 1.
此前我们报道了ABT - 627（1，A - 147627，A - 127722的活性对映体）的发现，它是一种基于2,4 - 二芳基取代吡咯烷 - 3 - 羧酸的内皮素受体A拮抗剂。该化合物与ETA受体结合的亲和力（Ki）为0.034 nM，对ETA受体与ETB受体的选择性为2000倍。我们扩展了该系列的构效关系研究，试图进一步提高ETA选择性。当1的对甲氧基苯基被正戊基取代时，所得拮抗剂3的ETB/ETA活性比大幅增加，但ETA亲和力降低。构效关系研究表明，该烷基的取代和几何结构以及苯并二氧杂环上的取代对于优化这一系列高ETA选择性拮抗剂很重要。特别是，（E） - 2,2 - 二甲基 - 3 - 戊烯基和7 - 甲氧基 - 1,3 - 苯并二氧杂环 - 5 - 基的组合提供了对人ETA受体亚型具有亚纳摩尔亲和力且ETB/ETA活性比超过130000的疏水性化合物10b。同时，在合成烯烃类化合物的过程中发现，用2 - 吡啶基乙基（9o）和2 - （2 - 氧代吡咯烷基）乙基（9u）取代1的对甲氧基苯基可得到亲水性很强的ETA拮抗剂，其效力和选择性与10b相当。基于总体上更优异的亲和力、对ETA受体的高选择性（ETA的Ki为0.46 nM，ETB的Ki为13000 nM）以及良好的口服生物利用度（大鼠体内为48%），A - 216546（10a）被选为1的潜在临床备用药物。
