Potential inhibitors of angiogenesis. Part I: 3-(imidazol-4(5)-ylmethylene)indolin-2-ones.
The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)indolin-2-ones, analogues of SU-5416, are reported. The final compounds 20-51 were obtained by Knoevenagel coupling between the substituted indolin-2-ones 1-15 and either the formylimidazole derivatives 16-18 or 2-formyl-3,5-dimethylpyrrole 19. Methylation at the nitrogen atom of the indolin-2-one and/or imidazole moities was carried out in the presence of the couple NaH/DMF. A Mannich reaction afforded the 1-dimethylaminomethyl derivatives 43 and 48. The antiangiogenic activity of these compounds was evaluated in a three dimensional in vitro rat aortic ring assay. In this test, compound 20 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density indexes at 1 microM were 30 +/- 18 and 22 +/- 4% of control, respectively. The compounds were also evaluated, in an independent manner, as inhibitors of the human EGF-receptor tyrosine kinase activity. As expected, only minor activities were observed with four compounds, out of thirty-one, exerting inhibitory effects in the range of 40-55% at 10 microM concentration.
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008745:Methylation; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D009584:Nitrogen