Download MendeleyStructural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38 alpha Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.
Ansideri, F., Macedo, J.T., Eitel, M., El-Gokha, A., Zinad, D.S., Scarpellini, C., Kudolo, M., Schollmeyer, D., Boeckler, F.M., Blaum, B.S., Laufer, S.A., Koch, P.(2018) ACS Omega 3: 7809-7831
- PubMed: 30087925
- DOI: https://doi.org/10.1021/acsomega.8b00668
- Primary Citation of Related Structures:
6EKD, 6EMH, 6EQ9 - PubMed Abstract:
Starting from known p38¦Á mitogen-activated protein kinase (MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained. Altering the substitution pattern of the pyridinylimidazole scaffold proved to be effective in shifting the inhibitory activity from the original target p38¦Á MAPK to the closely related JNK3. In particular, a significant improvement for JNK3 selectivity could be achieved by addressing the hydrophobic region I with a small methyl group. Furthermore, additional structural modifications permitted to explore structure-activity relationships. The most potent inhibitor 4-(4-methyl-2-(methylthio)-1 H -imidazol-5-yl)- N -(4-morpholinophenyl)pyridin-2-amine showed an IC 50 value for the JNK3 in the low triple digit nanomolar range and its binding mode was confirmed by X-ray crystallography.
Organizational Affiliation:
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universit?t T¨¹bingen, Auf der Morgenstelle 8, 72076 T¨¹bingen, Germany.
