title: Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630.
abstract: IRL 3630 (3), a single enantiomer of IRL 3461 with more potency was identified. Coupling reaction of the racemic fragment (1) with the chiral (L)-valinesulfonamide (2) under a biphasic solvent system (CH2Cl2-H2O) successfully led to the predominant formation of the desired isomer (3) with concomitant isomerization of 1. IRL 3630, N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-+ ++isoxazolyl) -phenyl]-(D)-alanyl]-(L)-valineamide, is a highly potent and bifunctional (ETA + ETB) antagonist [Ki(ETA) = 1.5 nM, Ki(ETB) = 1.2 nM].
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: K
authors.initials: K
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D007202:Indicators and Reagents; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009904:Optical Rotation; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D004151:Dipeptides; D065128:Endothelin Receptor Antagonists; D007202:Indicators and Reagents; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C116703:IRL 3461