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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2005-09, Vol.48 (19), p.5884-5887
Main Authors: 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: Article
Language:English
Subjects:
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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