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Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors.

ABSTRACT: A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC₅₀= 106?nM) with excellent selectivity profiles over 36 other protein kinases including cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC₅₀ value of 301?nM, and other FLT3 mutants showing potential as an AML therapeutics.

SUBMITTER: Im D

PROVIDER: S-EPMC7241567 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors.

Im Daseul D Moon Hyungwoo H Kim Jinwoong J Oh Youri Y Jang Miyoung M Hah Jung-Mi JM

Journal of enzyme inhibition and medicinal chemistry 20201201 1

A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC50= 106 nM) with excellent selecti ...[more]

PMID: 32338093

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