Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, Indiana 46202, United States.
J Med Chem. 2011 Oct 27;54(20):7193-205. doi: 10.1021/jm200782y. Epub 2011 Oct 4.
Virtual screening targeting the urokinase receptor (uPAR) led to (±)-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 IC(50) near 30 μM. Both compounds blocked angiogenesis with IC(50) of 3 μM. Compounds 2 and 3 inhibited cell growth with IC(50) of 6 and 18 μM and induced apoptosis. Biochemical assays revealed leadlike properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM 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.
针对尿激酶受体 (uPAR) 的虚拟筛选导致了 (±)-3-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(苯并[d][1,3]二氧杂环戊烯-5-基甲基)-4-苯基丁-1-胺 1 (IPR-1) 和 N-(3,5-二甲基苯基)-1-(4-异丙基苯基)-5-(哌啶-4-基)-1H-吡唑-4-甲酰胺 3 (IPR-69)。合成 1 的类似物，即 2 (IPR-9) 和 3，进行了 MDA-MB-231 乳腺癌侵袭、迁移和粘附试验，IC50 接近 30 μM。这两种化合物均以 3 μM 的 IC50 抑制血管生成。化合物 2 和 3 的细胞生长抑制 IC50 分别为 6 和 18 μM，并诱导细胞凋亡。生化试验表明 3 具有先导化合物的特性，但 2 没有。化合物 3 经口服给药后，其峰值浓度接近 40 μM，半衰期约为 2 小时。在 NOD-SCID 小鼠的乳腺脂肪垫中接种乳腺癌 TMD-231 细胞后，3 化合物使肿瘤体积减少了 20%，并且观察到治疗小鼠的转移范围较小。3 的适宜药代动力学特性和转移的令人鼓舞的初步结果使其成为下一代化合物的理想起点。
