title: Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents.
abstract: Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. samuel.chackalaminnil@spcorp.com
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Martin
authors.initials: M
authors.lastname: Clasby
authors.forename: Darìo
authors.initials: D
authors.lastname: Doller
authors.forename: Hsingan
authors.initials: H
authors.lastname: Tsai
authors.forename: Theodros
authors.initials: T
authors.lastname: Asberom
authors.forename: Michael
authors.initials: M
authors.lastname: Czarniecki
authors.forename: Ho-Sam
authors.initials: HS
authors.lastname: Ahn
authors.forename: George
authors.initials: G
authors.lastname: Boykow
authors.forename: Carolyn
authors.initials: C
authors.lastname: Foster
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Agans-Fantuzzi
authors.forename: Matthew
authors.initials: M
authors.lastname: Bryant
authors.forename: Janice
authors.initials: J
authors.lastname: Lau
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C505164:4-(5-(3-trifluoromethylphenyl)pyridin-2-yl)ethenyl-3-methyldecahydronaphtho(2,3-c)furan-1(3H)-one; D000470:Alkaloids; D005343:Fibrinolytic Agents; D005663:Furans; D006575:Heterocyclic Compounds, 3-Ring; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C048172:himbacine