title: 4-Benzothiazole-7-hydroxyindolinyl diaryl ureas are potent P2Y1 antagonists with favorable pharmacokinetics: low clearance and small volume of distribution.
abstract: Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.
authors.affiliation: Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, Rt. 206 and Province Line Road, Princeton, NJ 08543 (USA). Jennifer.qiao@bms.com.
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Sheldon
authors.initials: S
authors.lastname: Hiebert
authors.forename: Carol H
authors.initials: CH
authors.lastname: Hu
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Steven A
authors.initials: SA
authors.lastname: Spronk
authors.forename: Charles G
authors.initials: CG
authors.lastname: Clark
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.forename: Ji
authors.initials: J
authors.lastname: Hua
authors.forename: Laura A
authors.initials: LA
authors.lastname: Price
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Silvi A
authors.initials: SA
authors.lastname: Chacko
authors.forename: Gerry
authors.initials: G
authors.lastname: Everlof
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bostwick
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Steinbacher
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Li
authors.forename: Christine S
authors.initials: CS
authors.lastname: Huang
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.forename: Robert
authors.initials: R
authors.lastname: Rehfuss
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000818:Animals; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D058921:Purinergic P2Y Receptor Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D014508:Urea
keywords: P2Y1 antagonist; anionically active trifluoromethyl groups; antiplatelet; clearance; structure-activity relationships; volume of distribution