title: Discovery of 4-aryl-7-hydroxyindoline-based P2Y1 antagonists as novel antiplatelet agents.
abstract: Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target.
authors.affiliation: Discovery Chemistry, ‡Discovery Biology, and §Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research , Post Office Box 5400, Princeton, New Jersey 08643-5400, United States.
authors.forename: Wu
authors.initials: W
authors.lastname: Yang
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Amy
authors.initials: A
authors.lastname: Lai
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
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: Xue-qing
authors.initials: XQ
authors.lastname: Chen
authors.forename: Pancras
authors.initials: P
authors.lastname: Wong
authors.forename: Earl
authors.initials: E
authors.lastname: Crain
authors.forename: Carol
authors.initials: C
authors.lastname: Watson
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; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D007211:Indoles; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; C057812:indoline