Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents.
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.
Chackalamannil
Samuel
S
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. samuel.chackalaminnil@spcorp.com
Xia
Yan
Y
Greenlee
William J
WJ
Clasby
Martin
M
Doller
Darìo
D
Tsai
Hsingan
H
Asberom
Theodros
T
Czarniecki
Michael
M
Ahn
Ho-Sam
HS
Boykow
George
G
Foster
Carolyn
C
Agans-Fantuzzi
Jacqueline
J
Bryant
Matthew
M
Lau
Janice
J
Chintala
Madhu
M
D000284:Administration, Oral; D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C505164:4-(5-(3-trifluoromethylphenyl)pyridin-2-yl)ethenyl-3-methyldecahydronaphtho(2,3-c)furan-1(3H)-one; D000470:Alkaloids; D005343:Fibrinolytic Agents; D005663:Furans; D006575:Heterocyclic Compounds, 3-Ring; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C048172:himbacine