title: Himbacine derived thrombin receptor antagonists: discovery of a new tricyclic core.
abstract: The synthesis and biological activity of a novel series of thrombin receptor antagonists is described. This series of compounds showed excellent in vitro and in vivo potency. The most potent compound 40 had an IC(50) of 7.6 nM and showed robust inhibition of platelet aggregation in a cynomolgus monkey model after oral administration.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. martin.clasby@spcorp.com <martin.clasby@spcorp.com>
authors.forename: Martin C
authors.initials: MC
authors.lastname: Clasby
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Michael
authors.initials: M
authors.lastname: Czarniecki
authors.forename: Darío
authors.initials: D
authors.lastname: Doller
authors.forename: Keith
authors.initials: K
authors.lastname: Eagen
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Jayaram R
authors.initials: JR
authors.lastname: Tagat
authors.forename: Hsingan
authors.initials: H
authors.lastname: Tsai
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Ho-Sam
authors.initials: HS
authors.lastname: Ahn
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Agans-Fantuzzi
authors.forename: George
authors.initials: G
authors.lastname: Boykow
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McPhail
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D008252:Macaca fascicularis; D008956:Models, Chemical; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010276:Parasympatholytics / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013917:Thrombin / Q000737:chemistry
chemical_list: D000470:Alkaloids; D005663:Furans; D008024:Ligands; D009281:Naphthalenes; D010276:Parasympatholytics; D010880:Piperidines; D018179:Receptors, Thrombin; D013917:Thrombin; C048172:himbacine