Himbacine derived thrombin receptor antagonists: discovery of a new tricyclic core.
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.
Clasby
Martin C
MC
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. martin.clasby@spcorp.com <martin.clasby@spcorp.com>
Chackalamannil
Samuel
S
Czarniecki
Michael
M
Doller
Darío
D
Eagen
Keith
K
Greenlee
William J
WJ
Lin
Yan
Y
Tagat
Jayaram R
JR
Tsai
Hsingan
H
Xia
Yan
Y
Ahn
Ho-Sam
HS
Agans-Fantuzzi
Jacqueline
J
Boykow
George
G
Chintala
Madhu
M
Hsieh
Yunsheng
Y
McPhail
Andrew T
AT
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
D000470:Alkaloids; D005663:Furans; D008024:Ligands; D009281:Naphthalenes; D010276:Parasympatholytics; D010880:Piperidines; D018179:Receptors, Thrombin; D013917:Thrombin; C048172:himbacine