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 K i of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in...

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Veröffentlicht in:	Journal of medicinal chemistry 2005-09, Vol.48 (19), p.5884-5887
Hauptverfasser:	Chackalamannil, Samuel, Xia, Yan, Greenlee, William J, Clasby, Martin, Doller, Darìo, Tsai, Hsingan, Asberom, Theodros, Czarniecki, Michael, Ahn, Ho-Sam, Boykow, George, Foster, Carolyn, Agans-Fantuzzi, Jacqueline, Bryant, Matthew, Lau, Janice, Chintala, Madhu
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Alkaloids - chemical synthesis Alkaloids - chemistry Alkaloids - pharmacology Animals Biological and medical sciences Biological Availability Blood Platelets - drug effects Blood Platelets - metabolism Blood. Blood coagulation. Reticuloendothelial system Chromatography, High Pressure Liquid Cynomolgus Fibrinolytic Agents - chemical synthesis Fibrinolytic Agents - chemistry Fibrinolytic Agents - pharmacology Furans - chemical synthesis Furans - chemistry Furans - pharmacology Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Humans In Vitro Techniques Macaca fascicularis Medical sciences Naphthalenes - chemical synthesis Naphthalenes - chemistry Naphthalenes - pharmacology Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacology Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - chemistry Platelet Aggregation Inhibitors - pharmacology Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Radioligand Assay Rats Receptor, PAR-1 - antagonists & inhibitors Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	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 K i 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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm0502236