Wang, FangLi, JingSinn, Anthony L.Knabe, William EricKhanna, MayJo, InhaSilver, Jayne M.Oh, KyungsooLi, LiweiSandusky, George E.Sledge, George W.Nakshatri, HarikrishnaJones, David R.Pollok, Karen E.Meroueh, Samy O.2019-03-292019-03-292011-10-27Wang, F., Li, J., Sinn, A. L., Knabe, W. E., Khanna, M., Jo, I., … Meroueh, S. O. (2011). Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis. Journal of Medicinal Chemistry, 54(20), 7193–7205. https://doi.org/10.1021/jm200782yhttps://hdl.handle.net/1805/18728Virtual screening targeting the urokinase receptor (uPAR) led to (3R)-4-cyclohexyl-3-(hexahydrobenzo[d][1,3]dioxol-5-yl)-N-((hexahydrobenzo[d][1,3]dioxol-5-yl)methyl)butan-1-aminium 1 (IPR-1) and 4-(4-((3,5-dimethylcyclohexyl)carbamoyl)-2-(4-isopropylcyclohexyl)pyrazolidin-3-yl)piperidin-1-ium 3 (IPR-69). Synthesis of an analog of 1, namely 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC50 near 30 μM. Both compounds blocked angiogenesis with IC50 of 3 μM. Compounds 2 and 3 inhibited cell growth with IC50 of 6 and 18 μM and induced apoptosis. Biochemical assays revealed lead-like properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 hours. 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.en-USUrokinase ReceptorBreast TumormetastasisArticle10.1021/jm200782y0022-2623