SCH79797

SCH79797 is a highly potent, selective nonpeptide protease activated receptor 1 (PAR1) antagonist. SCH79797 inhibits binding of a high-affinity thrombin receptor-activating peptide to PAR1 with an IC₅₀ of 70 nM and a K_i of 35 nM. SCH79797 inhibits thrombin-induced platelet aggregation with an IC₅₀ of 3 μM. SCH79797 has antiproliferative and pro-apoptotic effects, and limits myocardial ischemia/reperfusion injury in rat hearts. SCH79797 also potently prevents PAR1 activation in vascular smooth muscle cells, endothelial cells, and astrocytes^[1][2][3][4]. IC50 & Target: Protease activated receptor 1 (PAR1)^[1]; Apoptosis^[3] In Vitro: SCH79797 inhibits high-affinity thrombin receptor-activating peptide ([³H]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 Ca²⁺ concentration ([Ca²⁺]_i) in hCASMC. SCH79797 effectively inhibits this increase in [Ca²⁺]_i. SCH79797 completely inhibits Thrombin- and TK-stimulated [³H]thymidine incorporation^[1].
SCH79797 is able to interfere with the growth of several human and mouse cell lines, in a concentration-dependent manner. The ED₅₀ 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^[2]. In Vivo: 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^[4].