title: Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity.
abstract: The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. samuel.chackalamannil@spcorp.com
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Wang
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Hu
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Ho-Sam
authors.initials: HS
authors.lastname: Ahn
authors.forename: George
authors.initials: G
authors.lastname: Boykow
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Jairam
authors.initials: J
authors.lastname: Palamanda
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Agans-Fantuzzi
authors.forename: Stan
authors.initials: S
authors.lastname: Kurowski
authors.forename: Michael
authors.initials: M
authors.lastname: Graziano
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D005663:Furans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D005663:Furans; D007783:Lactones; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin; C048172:himbacine; C530299:vorapaxar