Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity.
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.
Chackalamannil
Samuel
S
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. samuel.chackalamannil@spcorp.com
Wang
Yuguang
Y
Greenlee
William J
WJ
Hu
Zhiyong
Z
Xia
Yan
Y
Ahn
Ho-Sam
HS
Boykow
George
G
Hsieh
Yunsheng
Y
Palamanda
Jairam
J
Agans-Fantuzzi
Jacqueline
J
Kurowski
Stan
S
Graziano
Michael
M
Chintala
Madhu
M
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
D000470:Alkaloids; D005663:Furans; D007783:Lactones; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin; C048172:himbacine; C530299:vorapaxar