title: Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation.
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.
authors.affiliation: Departments 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.
authors.forename: Phanindra K M
authors.initials: PK
authors.lastname: Venukadasula
authors.affiliation: Departments 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.
authors.forename: Benjamin Y
authors.initials: BY
authors.lastname: Owusu
authors.affiliation: Departments 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.
authors.forename: Namita
authors.initials: N
authors.lastname: Bansal
authors.affiliation: Departments 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.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Ross
authors.affiliation: Departments 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.
authors.forename: Judith V
authors.initials: JV
authors.lastname: Hobrath
authors.affiliation: Departments 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.
authors.forename: Donghui
authors.initials: D
authors.lastname: Bao
authors.affiliation: Departments 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.
authors.forename: Jackie W
authors.initials: JW
authors.lastname: Truss
authors.affiliation: Departments 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.
authors.forename: Murray
authors.initials: M
authors.lastname: Stackhouse
authors.affiliation: The Wistar Institute , 3601 Spruce Street, Philadelphia, Pennsylvania19104, United States.
authors.forename: Troy E
authors.initials: TE
authors.lastname: Messick
authors.affiliation: Departments 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.
authors.forename: Lidija
authors.initials: L
authors.lastname: Klampfer
authors.affiliation: Departments 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.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
keywords: HGFA; SRI 31215; Serine protease; hepsin; iHGFa; matriptase; triplex protease inhibitor