title: Discovery of diarylurea P2Y(1) antagonists with improved aqueous solubility.
abstract: Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.
authors.affiliation: Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Charles G
authors.initials: CG
authors.lastname: Clark
authors.forename: Ji
authors.initials: J
authors.lastname: Jua
authors.forename: Laura A
authors.initials: LA
authors.lastname: Price
authors.forename: Qimin
authors.initials: Q
authors.lastname: Wu
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Joanna
authors.initials: J
authors.lastname: Zheng
authors.forename: Christine S
authors.initials: CS
authors.lastname: Huang
authors.forename: Gerry
authors.initials: G
authors.lastname: Everlof
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.forename: Anne B
authors.initials: AB
authors.lastname: Stewart
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bostwick
authors.forename: Earl J
authors.initials: EJ
authors.lastname: Crain
authors.forename: Carol A
authors.initials: CA
authors.lastname: Watson
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; D018938:Caco-2 Cells; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010314:Partial Thromboplastin Time; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D058472:Receptors, Purinergic P2Y1 / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy; D014508:Urea / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014867:Water / Q000737:chemistry
chemical_list: D005343:Fibrinolytic Agents; D010671:Phenylurea Compounds; D058921:Purinergic P2Y Receptor Antagonists; D011725:Pyridines; D058472:Receptors, Purinergic P2Y1; D014867:Water; D014508:Urea