Thrombin receptor (PAR-1) antagonists. Heterocycle-based peptidomimetics of the SFLLR agonist motif

The thrombin receptor (PAR-I) is activated by a-thrombin to stimulate various cell types, including platelets, through the tethered-ligand sequence SFLLRN. A series of azole-based carboxamides, designed after SFLLR, were synthesized and evaluated in vitro. The compounds inhibited platelet aggregation induced by SFLLRN-NH2 or a-thrombin, and blocked the binding of [H-3]-S-(p-F-Phe)-Har-L-Har-KY-NH2 to a CHRF membrane preparation of PAR-I. Oxazole 30 bound to PAR-I with an IC50 Of 1.6 mu M, and gave IC50 values of 25 mu M and 6.6 mu M against alpha-thrombin- and SFLLRN-NH2-induced platelet aggregation, respectively. (C) 1998 Elsevier Science Ltd. All rights reserved.