Discovery of 4-arylamido 3-methyl isoxazole derivatives as novel FMS kinase inhibitors

Abstract

A series of 4-arylamido 3-methyl isoxazoles were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Most compounds showed selective antiproliferative activity toward the U937 cell line and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide 5a-b, 6a-o and urea 7a-n, 8a-g with hydrophobic moieties, and one of the most potent inhibitor 6a, 5-methyl-N-(2-methyl-5-(3-(4-methylpiperazin-l-yl)-5-(trifluoromethyl)benzamido)pherwl)isoxazole-4-carboxamide was found to be very potent inhibitor of FMS kinase (GI(50) = 0.016 mu M, IC50 = 9.95 nM) with excellent selectivity profiles and is a promising candidate for further development in therapeutics for cancer. (C) 2015 Elsevier Masson SAS. All rights reserved.