Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease

Significant data exists to suggest
that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator
of neuronal degeneration following neuronal injury and in chronic
neurodegenerative disease. Consequently, there is considerable interest
in the identification of DLK inhibitors with a profile compatible
with development for these indications. Herein, we use structure-based
drug design combined with a focus on CNS drug-like properties to generate
compounds with superior kinase selectivity and metabolic stability
as compared to previously disclosed DLK inhibitors. These compounds,
exemplified by inhibitor 14, retain excellent CNS penetration
and are well tolerated following multiple days of dosing at concentrations
that exceed those required for DLK inhibition in the brain.