Synthesis of novel peptide inhibitors of thrombin-induced platelet activation.

Inhibitors of the activation of platelet aggregation have promise as important therapeutic agents for the management of acute coronary syndrome (ACS). Platelet activation by thrombin, a serine protease, occurs by binding to and cleavage of the extracellular N-terminal domains of protease-activated receptors 1 and 4 (PAR1 and PAR4). The proteolysis of the PARs exposes new tethered ligands that then signal through transmembrane domains to initiate platelet activation as a downstream effect. A pentapeptide cleavage product of bradykinin with the sequence Arg-Pro-Pro-Gly-Phe serves as a thrombin inhibitor by blocking alpha- and gamma-thrombin-induced platelet aggregation. Analogs of RPPGF have been prepared that result in improved inhibition of thrombin activation of platelets. Specific amino acid residues required for activity against platelet aggregation have been identified, and a lead compound, rOicPaPhe(p-Me)-NH(2) (FM19), has been developed. FM19, which completely inhibits threshold gamma-thrombin-induced platelet aggregation at a concentration of 16 +/- 4 microm, represents an important lead compound in the development of inhibitors of thrombin-mediated platelet aggregation for treatment of ACS.