title: Discovery of nor-seco himbacine analogs as thrombin receptor antagonists.
abstract: Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.
authors.affiliation: Central Nervous System and Cardiovascular Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Joseph.Warmus@Pfizer.com
authors.forename: Mariappan V
authors.initials: MV
authors.lastname: Chelliah
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Keith
authors.initials: K
authors.lastname: Eagen
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
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: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Matthew
authors.initials: M
authors.lastname: Bryant
authors.forename: Tze-Ming
authors.initials: TM
authors.lastname: Chan
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D055808:Drug Discovery; D005663:Furans / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D008252:Macaca fascicularis; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism
chemical_list: D000470:Alkaloids; D005663:Furans; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D013917:Thrombin; C048172:himbacine