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

• Published in: European journal of medicinal chemistry Vol. 102; pp. 600 - 610
• Main Authors: Im, Daseul, Jung, Kyungjin, Yang, Songyi, Aman, Waqar, Hah, Jung-Mi
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 18.09.2015; Elsevier
• Subjects: 4-arylamido 3-methyl isoxazoles; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Hematopoietic cell line; Humans; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Kinase inhibitor; Kinase selectivity; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Science & Technology; Structure-Activity Relationship; U937 Cells; Antiproliferative activity; Kinase inhibitor; Hematopoietic cell line; 4-arylamido 3-methyl isoxazoles; Kinase selectivity; TARGET; DESIGN
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.08.031

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-1-yl)-5-(trifluoromethyl)benzamido)phenyl)isoxazole-4-carboxamide was found to be very potent inhibitor of FMS kinase (GI50 = 0.016 μM, IC50 = 9.95 nM) with excellent selectivity profiles and is a promising candidate for further development in therapeutics for cancer. [Display omitted] •We synthesized 4-arylamido 3-methyl isoxazoles as potential protein kinase inhibitor.•We found their potent antiproliferative activities on U937 hematopoietic cell line.•The most potent inhibitor was found to be a potent and selective FMS inhibitor.