Synthesis, Biological Evaluation, X-ray Structure, and Pharmacokinetics of Aminopyrimidine c-jun-N-terminal Kinase (JNK) Inhibitors

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 pharmacokinctics in rats were also measured. Compounds 9g, 9i, 9j, and 91 had greater than 135-fold selectivity over p38, and cell-based IC50 values < 100 nM. Moreover, compound 91 showed an IC50 = 0.8 nM for inhibition of ROS and had good pharmacokinctic properties in rats along with a brain-to-plasma ratio of 0.75. These results Suggest that biaryl substituted aminopyrimidines represented by compound 91 may serve as the First small molecule inhibitors to test efficacy of JNK inhibitors in neurodegenerative disorders.