title: Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1).
abstract: The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. phillipe_nantermet@merck.com
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: George F
authors.initials: GF
authors.lastname: Lundell
authors.forename: Janetta M
authors.initials: JM
authors.lastname: Pellicore
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Rittle
authors.forename: MaryBeth
authors.initials: M
authors.lastname: Young
authors.forename: Roger M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Connolly
authors.forename: Cindra
authors.initials: C
authors.lastname: Condra
authors.forename: Jerzy
authors.initials: J
authors.lastname: Karczewski
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Gaul
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gould
authors.forename: Kris
authors.initials: K
authors.lastname: Prendergast
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
mesh_terms: D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: C456400:5-(3-(hexahydroazepin-1-yl)propyl)(benzodioxol-5-yl)amino-3-(3,5-difluorophenyl)isoxazole; D001381:Azepines; D007202:Indicators and Reagents; D007555:Isoxazoles; D010446:Peptide Fragments; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C072032:thrombin receptor peptide (42-55); D013917:Thrombin