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Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3.
- Source :
-
Journal of Medicinal Chemistry . Jan2017, Vol. 60 Issue 2, p594-607. 14p. - Publication Year :
- 2017
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222623
- Volume :
- 60
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 120976175
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01180