Design, Synthesis, and Evaluations of Substituted 3-[(3- or 4-Carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as Inhibitors of VEGF, FGF, and PDGF Receptor Tyrosine Kinases

Abstract

Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain-containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC(50) values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC(50) values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC(50) value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.

Modeling human tumor angiogenesis in a three-dimensional culture system

“…[27][28][29][30] Elevated sensitivity to antiangiogenic drugs of the hAR assay was confirmed by comparative experiments using the murine model, in which the antiangiogenic effects of Sunitinib and PI-103 (supplemental Figure 6C), in terms of IC50, were 1.8 nM and 2.1 mM, respectively ( Figure 3B and supplemental Figure 6D). Therefore, the hAR model proved to be twice more sensitive to the tested angiogenic inhibitors than the mAR model ( Figure 3B).…”

Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome

“…Vatalanib was prepared according to the published procedure (11). THRX-165724 was prepared by coupling piperazine to the carboxyl group of SU6668 (12).…”

Potential Inhibitors of Angiogenesis. Part I: 3-(Imidazol-4(5)-ylmethylene)indolin-2-ones

“…Chemistry 3-(Imidazol-4(5)-ylmethylene)indolin-2-ones 20 -51 were prepared by the Knoevenagel reaction, (see Figure 3), by condensation of the formyl derivatives 16 -19 with indolin-2-ones 1-15 in the presence of piperidine and in refluxing ethanol following a method previously reported by Andreani et al 35,36 Indolin-2-ones 2 -15 were obtained by reduction of isatines or 3-methylthioindolinone from the corresponding anilines 19,25 or by reduction of 2-nitrophenylacetic acids 23,24 or N-methoxyphenylacetamides. 20 -22 Compounds 20 -40, monomethylated at the N 1 -imidazole ring, were obtained starting from 17 or 18.…”

“…22 The 6-phenyl-and 6-trifluoromethylindolin-2-ones, 8 and 9, were prepared from the corresponding 2-nitrophenylacetic acids. 23,24 4-Aminoindolin-2-one 10 was obtained by hydrogenolysis of the 3-methylthioindolin-2-one. 25 Acetamide 11 was prepared by direct acetylation of 10.…”