Protease-activated receptor 1-selective antagonist SCH79797 inhibits cell proliferation and induces apoptosis by a protease-activated receptor 1-independent mechanism.

Abstract:   Thrombin, a key mediator of blood coagulation, exerts a large number of cellular actions via activation of a specific G-protein-coupled receptor, named protease-activated receptor 1 (PAR1). Several studies in experimental animals have demonstrated a therapeutic potential of small molecules with PAR1 antagonistic properties for treatment of diseases such as vascular thrombosis and arterial restenosis. We have studied the biological actions of one highly potent, selective PAR1 antagonist, SCH79797 (N 3-cyclopropyl-7-{[4-(1-methylethyl)phenyl]methyl}-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine), in vitro, and found that this compound was able to interfere with the growth of several human and mouse cell lines, in a concentration-dependent manner. The ED50 for growth inhibition was 75 nM, 81 nM and 116 nM for NIH 3T3, HEK 293 and A375 cells, respectively. Moreover, in NIH 3T3 cells, SCH79797 inhibited serum-stimulated activation of p44/p42 mitogen-activated protein kinases (MAPK) at low concentrations and induced apoptosis at higher concentrations. However, the antiproliferative and pro-apoptotic effects of SCH79797 are likely not mediated by PAR1 antagonism, as they were also observed in embryonic fibroblasts derived from PAR1 null mice. These data suggest that, in view of the development of PAR1-selective antagonists as therapeutic agents, effects potentially unrelated to PAR1 inhibition should be carefully scrutinized.