1. Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1).
- Author
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Nantermet PG, Barrow JC, Lundell GF, Pellicore JM, Rittle KE, Young M, Freidinger RM, Connolly TM, Condra C, Karczewski J, Bednar RA, Gaul SL, Gould RJ, Prendergast K, and Selnick HG
- Subjects
- Blood Platelets drug effects, Drug Design, Humans, In Vitro Techniques, Indicators and Reagents, Peptide Fragments antagonists & inhibitors, Peptide Fragments pharmacology, Piperidines chemical synthesis, Piperidines chemistry, Platelet Activation drug effects, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors chemical synthesis, Platelet Aggregation Inhibitors pharmacology, Receptor, PAR-1, Structure-Activity Relationship, Thrombin antagonists & inhibitors, Azepines chemical synthesis, Azepines pharmacology, Blood Platelets metabolism, Isoxazoles chemical synthesis, Isoxazoles pharmacology, Receptors, Thrombin antagonists & inhibitors
- Abstract
The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.
- Published
- 2002
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