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In this letter we report first nonpeptide inhibitors of hepatocyte growth factor (HGF) activation. These compounds inhibit the three proteases (matriptase, hepsin, and HGF activator) required for HGF maturation. We show that 6, 8a, 8b, and 8d block activation of fibroblast-derived pro-HGF, thus preventing fibroblast-induced scattering of DU145 prostate cancer cells. Compound 6 (SRI 31215) is very soluble (91 μM) and has excellent microsome stability (human t_1/2 = 162 min; mouse t_1/2 = 296 min). In mouse 6 has an in vivo t_1/2 = 5.8 h following IV administration. The high solubility of 6 and IV t_1/2 make this compound a suitable prototype “triplex inhibitor” for the study of the inhibition of HGF activation in vivo.