肝细胞生长因子激活的非肽类抑制剂的设计与合成
Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation.
作者信息
Venukadasula Phanindra K M, Owusu Benjamin Y, Bansal Namita, Ross Larry J, Hobrath Judith V, Bao Donghui, Truss Jackie W, Stackhouse Murray, Messick Troy E, Klampfer Lidija, Galemmo Robert A
机构信息
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.
The Wistar Institute , 3601 Spruce Street, Philadelphia, Pennsylvania19104, United States.
出版信息
ACS Med Chem Lett. 2015 Dec 22;7(2):177-81. doi: 10.1021/acsmedchemlett.5b00357. eCollection 2016 Feb 11.
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.
摘要
在本信函中，我们报道了肝细胞生长因子（HGF）激活的首批非肽类抑制剂。这些化合物抑制HGF成熟所需的三种蛋白酶（matriptase、hepsin和HGF激活剂）。我们表明，6、8a、8b和8d可阻断成纤维细胞衍生的前HGF的激活，从而防止成纤维细胞诱导的DU145前列腺癌细胞散射。化合物6（SRI 31215）具有很高的溶解度（91 μM），并且具有出色的微粒体稳定性（人t1/2 = 162分钟；小鼠t1/2 = 296分钟）。在小鼠体内，静脉注射后6的体内t1/2 = 5.8小时。6的高溶解度和静脉注射t1/2使其成为用于体内研究HGF激活抑制的合适的原型“三联体抑制剂”。
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本文引用的文献
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2
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