Unknown

Dataset Information

0

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 ?M. Both compounds blocked angiogenesis with IC(50) of 3 ?M. Compounds 2 and 3 inhibited cell growth with IC(50) of 6 and 18 ?M and induced apoptosis. Biochemical assays revealed leadlike properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 ?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.

SUBMITTER: Wang F 

PROVIDER: S-EPMC3280887 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Wang Fang F   Li Jing J   Sinn Anthony L AL   Knabe W Eric WE   Khanna May M   Jo Inha I   Silver Jayne M JM   Oh Kyungsoo K   Li Liwei L   Sandusky George E GE   Sledge George W GW   Nakshatri Harikrishna H   Jones David R DR   Pollok Karen E KE   Meroueh Samy O SO  

Journal of medicinal chemistry 20111004 20


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  ...[more]

Similar Datasets

| S-EPMC3437670 | biostudies-literature
| S-EPMC3073583 | biostudies-literature
| S-EPMC3826001 | biostudies-literature
| S-EPMC6522927 | biostudies-literature
| S-EPMC4083208 | biostudies-literature
| S-EPMC3310947 | biostudies-literature
| S-EPMC9977057 | biostudies-literature
| S-EPMC9976450 | biostudies-literature
| S-EPMC10743089 | biostudies-literature
| S-EPMC3946838 | biostudies-literature