Virtual screening targeting the urokinase receptor, biochemical and cell-based studies, synthesis, pharmacokinetic characterization, and effect on breast tumor metastasis.

Abstract

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.

• Authors: 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, Harikrishna Nakshatri, David R Jones, Karen E Pollok, Samy O Meroueh
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 20 Pg. 7193-205 (Oct 27 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21851064 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Anilides
• Antineoplastic Agents
• Matrix Metalloproteinase Inhibitors
• N-(3,5-dimethylphenyl)-1-(4-isopropylphenyl)-5-(piperidin-4-yl)-1H-pyrazole-4-carboxamide
• Pyrazoles
• Receptors, Urokinase Plasminogen Activator

Topics

• Angiogenesis Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Anilides (chemical synthesis, pharmacokinetics, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Databases, Factual
• Drug Screening Assays, Antitumor
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Matrix Metalloproteinase Inhibitors
• Mice
• Mice, SCID
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Transplantation
• Pyrazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Receptors, Urokinase Plasminogen Activator (metabolism)
• Signal Transduction
• Structure-Activity Relationship
• Transplantation, Heterologous