title: Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ET(A) receptor selectivity.
abstract: Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity.
authors.affiliation: Metabolic Disease Research, Abbott Laboratories, Pharmaceutical Products Division, Abbott Park, IL 60064-6101, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Boyd
authors.forename: R A
authors.initials: RA
authors.lastname: Mantei
authors.forename: A S
authors.initials: AS
authors.lastname: Tasker
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: B K
authors.initials: BK
authors.lastname: Sorensen
authors.forename: K J
authors.initials: KJ
authors.lastname: Henry
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: M
authors.initials: M
authors.lastname: Winn
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: C W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: B
authors.initials: B
authors.lastname: Nguyen
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
mesh_terms: D000818:Animals; D000077868:Atrasentan; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship
chemical_list: D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; C032519:pyrrolidine; D000077868:Atrasentan