title: Identification of 1-{2-[4-chloro-1'-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y(1) antagonist as an antiplatelet agent.
abstract: Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Yoon T
authors: YT
authors: Jeon
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: wu.yang@bms.com.
authors: Wu
authors: W
authors: Yang
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: jennifer.qiao@bms.com.
authors: Jennifer X
authors: JX
authors: Qiao
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Ling
authors: L
authors: Li
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Rejean
authors: R
authors: Ruel
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Carl
authors: C
authors: Thibeault
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Sheldon
authors: S
authors: Hiebert
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Tammy C
authors: TC
authors: Wang
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Yufeng
authors: Y
authors: Wang
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Yajun
authors: Y
authors: Liu
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Charles G
authors: CG
authors: Clark
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Henry S
authors: HS
authors: Wong
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Juliang
authors: J
authors: Zhu
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Dauh-Rurng
authors: DR
authors: Wu
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Dawn
authors: D
authors: Sun
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Bang-Chi
authors: BC
authors: Chen
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Arvind
authors: A
authors: Mathur
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Silvi A
authors: SA
authors: Chacko
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Mary
authors: M
authors: Malley
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Xue-Qing
authors: XQ
authors: Chen
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Hong
authors: H
authors: Shen
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Christine S
authors: CS
authors: Huang
authors: Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: William A
authors: WA
authors: Schumacher
authors: Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Jeffrey S
authors: JS
authors: Bostwick
authors: Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Anne B
authors: AB
authors: Stewart
authors: Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Laura A
authors: LA
authors: Price
authors: Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Ji
authors: J
authors: Hua
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Danshi
authors: D
authors: Li
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Paul C
authors: PC
authors: Levesque
authors: Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Dietmar A
authors: DA
authors: Seiffert
authors: Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Robert
authors: R
authors: Rehfuss
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Ruth R
authors: RR
authors: Wexler
authors: Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors: Patrick Y S
authors: PY
authors: Lam
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D006207:Half-Life; D008252:Macaca fascicularis; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D058472:Receptors, Purinergic P2Y1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010671:Phenylurea Compounds; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D013844:Thiazoles; D014508:Urea
keywords: Antiplatelet agent; P2Y(1) antagonist; Spiropiperidinylindolines