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

Article abstract of DOI:10.1016/S0960-894X(98)00292-3

The thrombin receptor (PAR-1) is activated by α-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 α-thrombin, and blocked the binding of [³H]-S-(p-F-Phe)-Har-L-Har-KY-NH₂ to a CHRF membrane preparation of PAR-1. Oxazole 30 bound to PAR-1 with an IC₅₀ of 1.6 μM, and gave IC₅₀ values of 25 μM and 6.6 μM against α-thrombin- and SFLLRN-NH₂-induced platelet aggregation, respectively.