title: Discovery of IRL 3461: a novel and potent endothelin antagonist with balanced ETA/ETB affinity.
abstract: IRL 3461, N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-+ ++isoxazolyl) -phenyl]-alanyl]-(L)-valineamide, a potent and bifunctional (ETA + ETB) [Ki(ETA) = 1.8 nM, Ki(ETB) = 1.2 nM] antagonist was discovered by structural modification of IRL 2500, an ETB selective antagonist. IRL 3461 was found to be stable on incubation with human, rat, mouse, and guinea pig plasmas.
authors.affiliation: Takarazuka Research Institute, Novartis Pharma K.K., Japan.
authors.forename: J
authors.initials: J
authors.lastname: Sakaki
authors.forename: T
authors.initials: T
authors.lastname: Murata
authors.forename: Y
authors.initials: Y
authors.lastname: Yuumoto
authors.forename: I
authors.initials: I
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Trueh
authors.forename: T
authors.initials: T
authors.lastname: Pitterna
authors.forename: G
authors.initials: G
authors.lastname: Iwasaki
authors.forename: K
authors.initials: K
authors.lastname: Oda
authors.forename: T
authors.initials: T
authors.lastname: Yamamura
authors.forename: K
authors.initials: K
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D004151:Dipeptides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D015195:Drug Design; D065128:Endothelin Receptor Antagonists; D006168:Guinea Pigs; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D004151:Dipeptides; D065128:Endothelin Receptor Antagonists; C098287:IRL 2500; D007202:Indicators and Reagents; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C116703:IRL 3461