SCH79797 DIHYDROCHLORIDE

Protease activated receptor 1 (PAR1); Apoptosis

SCH79797 inhibits high-affinity thrombin receptor-activating peptide ([ ³ H]haTRAP) binding in a competitive manner. SCH79797 inhibits α-thrombin- and haTRAP-induced aggregation of human platelets, but does not inhibit human platelet aggregation induced by the tethered ligand agonist for protease-activated receptor-4 (PAR-4), γ-thrombin, ADP, or collagen. Thrombin produces transient increases in cytosolic free Ca ²⁺ concentration ([Ca ²⁺ ] _i ) in hCASMC. SCH79797 effectively inhibits this increase in [Ca ²⁺ ] _i . SCH79797 completely inhibits Thrombin- and TK-stimulated [ ³ H]thymidine incorporation .
SCH79797 is able to interfere with the growth of several human and mouse cell lines, in a concentration-dependent manner. The ED ₅₀ for growth inhibition iss 75 nM, 81 nM and 116 nM for NIH 3T3, HEK 293 and A375 cells, respectively. In NIH 3T3 cells, SCH79797 inhibits serum-stimulated activation of p44/p42 mitogen-activated protein kinases (MAPK) at low concentrations and induces apoptosis at higher concentrations.

SCH79797 (2.5-250 μg/kg; intravenous injection; male Sprague Dawley rats) treatment immediately before or during ischemia reduces myocardial necrosis following I/R in the intact rat heart in two rat models of myocardial ischemia/reperfusion (I/R) injury. This response is dose-dependent with the optimal dose being 25 μg/kg.