Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c‑Jun N‑Terminal Kinase 3
The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure–activity relationships. Joint targeting of the hydrophobic region I and methy...
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Veröffentlicht in: | Journal of medicinal chemistry 2017-01, Vol.60 (2), p.594-607 |
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Hauptverfasser: | , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure–activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off-targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC50 = 0.3 nM), shows high metabolic stability in human liver microsomes, and displays excellent selectivity in a screening against a panel of 410 kinases. Covalent bond formation to Cys-154 was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry. |
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ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/acs.jmedchem.6b01180 |