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-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.

• Authors: Daseul Im, Kyungjin Jung, Songyi Yang, Waqar Aman, Jung-Mi Hah
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 102 Pg. 600-10 (Sep 18 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26318067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Isoxazoles
• Protein Kinase Inhibitors
• Protein Kinases

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Humans
• Isoxazoles (chemical synthesis, chemistry, pharmacology)
• Molecular Docking Simulation
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Protein Kinases (metabolism)
• Structure-Activity Relationship
• U937 Cells