PDB 3KVX deposited: 2009-11-30 modified: 2011-07-13
Title JNK3 bound to aminopyrimidine inhibitor, SR-3562
Authors Cameron, M.D., Chambers, J., Chen, W., Duckett, D., Figuera-Losada, M., Habel, J., Jiang, R., Kamenecka, T., Laughlin, J.D., Ling, Y.Y., Lin, L., Lograsso, P.V., Ruiz, C.H., Song, X.
Structure factors resolution 2.4 rfactor 0.21957 rfree 0.26933
DPI 0.99 theoretical min: 0.34

Given the significant body of data supporting an essential role for c-jun-N-terminal kinase (JNK) in neurodegenerative disorders, we set out to develop highly selective JNK inhibitors with good cell potency and good brain penetration properties. The structure-activity relationships (SAR) around a series of aminopyrimidines were evaluated utilizing biochemical and cell-based assays to measure JNK inhibition and brain penetration in mice. Microsomal stability in three species, P450 inhibition, inhibition of generation of reactive oxygen species (ROS), and pharmacokinetics in rats were also measured. Compounds 9g, 9i, 9j, and 9l had greater than 135-fold selectivity over p38, and cell-based IC(50) values < 100 nM. Moreover, compound 9l showed an IC(50) = 0.8 nM for inhibition of ROS and had good pharmacokinetic properties in rats along with a brain-to-plasma ratio of 0.75. These results suggest that biaryl substituted aminopyrimidines represented by compound 9l may serve as the first small molecule inhibitors to test efficacy of JNK inhibitors in neurodegenerative disorders.

J.Med.Chem. 2010 Jan; 53(1):419-431 doi:10.1021/jm901351f

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1156783
PubMed 19947601 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3KVX/0 3KVX 0 monomer 0 1 1 2276