title: 2,4-Diarylpyrrolidine-3-carboxylic acids--potent ETA 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.
authors.affiliation: Abbott Laboratories, Aging and Degenerative Diseases Research and Drug Analysis Department, Pharmaceutical Products Division, Abbott Park, Illinois 60064, USA.
authors.forename: M
authors.initials: M
authors.lastname: Winn
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
authors.forename: H S
authors.initials: HS
authors.lastname: Jae
authors.forename: A S
authors.initials: AS
authors.lastname: Tasker
authors.forename: S A
authors.initials: SA
authors.lastname: Boyd
authors.forename: J A
authors.initials: JA
authors.lastname: Kester
authors.forename: R A
authors.initials: RA
authors.lastname: Mantei
authors.forename: R
authors.initials: R
authors.lastname: Bal
authors.forename: B K
authors.initials: BK
authors.lastname: Sorensen
authors.forename: J R
authors.initials: JR
authors.lastname: Wu-Wong
authors.forename: W J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: D B
authors.initials: DB
authors.lastname: Dixon
authors.forename: E I
authors.initials: EI
authors.lastname: Novosad
authors.forename: L
authors.initials: L
authors.lastname: Hernandez
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology; D000077868:Atrasentan; D001682:Biological Availability; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006868:Hydrolysis; D008297:Male; D015394:Molecular Structure; D010716:Phosphatidylinositols / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D017466:Receptors, Endothelin; D000077868:Atrasentan