Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

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• 作者：Fang Wang ; Jing Li ; Anthony L. Sinn ; W. Eric Knabe ; May Khanna ; Inha Jo ; Jayne M. Silver ; Kyungsoo Oh ; Liwei Li ; George E. Sandusky ; George W. Sledge ; Jr. ; Harikrishna Nakshatri ; David R. Jones ; Karen E. Pollok ; Samy O. Meroueh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7193-7205
• 全文大小：1266K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

Virtual screening targeting the urokinase receptor (uPAR) led to (卤)-3-(benzo[d][1,3]dioxol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-phenylbutan-1-amine 1 (IPR-1) and N-(3,5-dimethylphenyl)-1-(4-isopropylphenyl)-5-(piperidin-4-yl)-1H-pyrazole-4-carboxamide 3 (IPR-69). Synthesis of an analogue of 1, namely, 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC₅₀ near 30 渭M. Both compounds blocked angiogenesis with IC₅₀ of 3 渭M. Compounds 2 and 3 inhibited cell growth with IC₅₀ of 6 and 18 渭M and induced apoptosis. Biochemical assays revealed leadlike properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 渭M with a half-life of about 2 h. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds.