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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of medicinal chemistry 2017-01, Vol.60 (2), p.594-607
Hauptverfasser: Muth, Felix, El-Gokha, Ahmed, Ansideri, Francesco, Eitel, Michael, Döring, Eva, Sievers-Engler, Adrian, Lange, Andreas, Boeckler, Frank M, Lämmerhofer, Michael, Koch, Pierre, Laufer, Stefan A
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01180