Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant <i>N</i> -(1 <i>H</i> -Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)

Abstract

Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.