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Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation
Phanindra K M Venukadasula1, Benjamin Y Owusu1, Namita Bansal1
1Departments of Chemistry, Oncology and High Throughput Screening, Drug Discovery Division, and Toxicology and Pathology Services, Drug Development Division, Southern Research , 2000 Ninth Avenue S., Birmingham, Alabama 35205, United States.
Abstract:
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.
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