Author/Authors :
Philippe G. Nantermet، نويسنده , , James C. Barrow، نويسنده , , George F. Lundell، نويسنده , , Janetta M. Pellicore، نويسنده , , Kenneth E. Rittle، نويسنده , , MaryBeth Young، نويسنده , , Roger M. Freidinger، نويسنده , , Thomas M. Connolly، نويسنده , , Cindra Condra، نويسنده , , Jerzy Karczewski، نويسنده , , Rodney A. Bednar، نويسنده , , Stanley L. Gaul، نويسنده , , Robert J. Gould، نويسنده , , Kris Prendergast، نويسنده , , Harold G. Selnick، نويسنده ,
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 IC50s 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.
