title: Pyrrolidine-3-carboxylic acids as endothelin antagonists. 5. Highly selective, potent, and orally active ET(A) antagonists.
abstract: The synthesis and structure-activity relationships (SAR) of a series of pyrrolidine-3-carboxylic acids as endothelin antagonists are described. The data shows an increase in selectivity when the methoxy of Atrasentan (ABT-627) is replaced with methyl, and the benzodioxole is replaced with dihydrobenzofuran. Adding a fluorine further increases the binding activity and provides a metabolically stable and orally bioavailable ET(A)-selective antagonist.
authors.affiliation: Metabolic Diseases Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. hwan-soo.jae@abbott.com
authors.forename: H S
authors.initials: HS
authors.lastname: Jae
authors.forename: M
authors.initials: M
authors.lastname: Winn
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: B K
authors.initials: BK
authors.lastname: Sorensen
authors.forename: W J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: B
authors.initials: B
authors.lastname: Nguyen
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044022:Receptor, Endothelin A; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C439966:2-(3-fluoro-4-methylphenyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; D001572:Benzofurans; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A