Design, synthesis, and evaluations of substituted 3-[(3-or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGFreceptor tyrosine kinases

Receptor tyrosine kinases (RTKs) have been implicated as therapeutic target s for the treatment of human diseases including cancers, inflammatory disea ses, cardiovascular diseases including arterial restenosis, and fibrotic di seases of the lung, liver, and kidney. Three classes of 3-substituted indol in-2-ones containing propionic acid functionality attached to the pyrrole r ing at the C-3 position of the core have been identified as catalytic inhib itors of the vascular endothelial growth factor (VEGF), fibroblast growth f actor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the co mpounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liv er tyrosine kinase 1 (Flk-1)/kinase insert domain-containing receptor (KDR) ], fibroblast growth factor receptor (FGF-R), and platelet-derived growth f actor receptor (PDGF-R) tyrosine kinase with IC50 values at nanomolar level . Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity With IC50 values of 20 and 30 nM, respectively, w hile compound 16f inhibited the PDGF-R tyrosine kinase activity with IC50 v alue of 10 nM. Structural models and structure-activity relationship analys is of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation as says as measured by bromodeoxyuridine (BrdU) incorporation. Specific and po tent inhibition of cell growth was observed for some of these compounds. Th ese data provide evidence that these compounds can be used to inhibit the f unction of these target receptors.