2,4-Diarylpyrrolidine-3-carboxylic AcidsPotent ET_A Selective Endothelin Receptor Antagonists. 1. Discovery of A-127722

Abstract

We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indian ring in SB 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrroli din e-3- carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC(50)=0.36 nM for inhibition of ET-1 radioligand binding at the ET(A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC(50)=0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-1-induced contraction of the rabbit aorta with a pA(2)=9.20. The compound has 70% oral bioavailability in rats.

Role of ET-1 receptor binding and [Ca2+]i in contraction of coronary arteries from DOCA-salt hypertensive rats

“…This range of vessel ID was selected to correlate with the intraluminal diameter of arteries used for receptor binding assays and for smooth muscle cell isolation. Concentration-response curves to ET-1 (1 ϫ 10 Ϫ11 to 3 ϫ 10 Ϫ8 M) were performed in the absence or presence of the selective ETA receptor antagonist A-127722 (30 nM) (34). A-127722 was added to the vessel bath 30 min before the concentration-response curve to ET-1 was performed.…”

RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum

“…In these experiments, tissues were preincubated with 10 M N G -nitro-L-arginine methyl ester (L-NAME) for 10 min before a cumulative (PE or ET-1) dose-response experiment was initiated. For ET A-receptor blockade, 30 nM A-127722 (25,33) was introduced to each bath 10 min before the addition of ET-1 or PE.…”

Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

“…(14)), which were then also evaluated by Winn et al (Abbott) [101] for binding at ET A and ET B receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activities and compounds with N -alkyl substituent containing ethers, sulfoxides or sulfones showed increased activities.…”

“…On the basis of the earlier studies [101,106] von Geldern and co-workers continued to explore the conformational restriction as a route to improving the selectivity of the compounds of pyrrolidine class. An unexpected result led them to observe [107] that a 2,6-dialkyl acetanilide side chain imparts ET B selectivity to this family.…”