title: Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist.
abstract: Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Réjean
authors.initials: R
authors.lastname: Ruel
authors.forename: Carl
authors.initials: C
authors.lastname: Thibeault
authors.forename: Alexandre
authors.initials: A
authors.lastname: L'Heureux
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Steven A
authors.initials: SA
authors.lastname: Spronk
authors.forename: Sheldon
authors.initials: S
authors.lastname: Hiebert
authors.forename: Gilles
authors.initials: G
authors.lastname: Bouthillier
authors.forename: John
authors.initials: J
authors.lastname: Lloyd
authors.forename: Zulan
authors.initials: Z
authors.lastname: Pi
authors.forename: Dora M
authors.initials: DM
authors.lastname: Schnur
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Abell
authors.forename: Ji
authors.initials: J
authors.lastname: Hua
authors.forename: Laura A
authors.initials: LA
authors.lastname: Price
authors.forename: Eddie
authors.initials: E
authors.lastname: Liu
authors.forename: Qimin
authors.initials: Q
authors.lastname: Wu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Steinbacher
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bostwick
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Joanna
authors.initials: J
authors.lastname: Zheng
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Baoqing
authors.initials: B
authors.lastname: Ma
authors.forename: Patricia A
authors.initials: PA
authors.lastname: McDonnell
authors.forename: Christine S
authors.initials: CS
authors.lastname: Huang
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; D001682:Biological Availability; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010671:Phenylurea Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014508:Urea / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: C586006:1-(2-(1'-neopentylspiro(indoline-3,4'-piperidine)-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea; D007211:Indoles; D010671:Phenylurea Compounds; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D013141:Spiro Compounds; C057812:indoline; D014508:Urea