Journal of Medicinal Chemistry · 2017 · 73 citations · 21 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryNeurodegenerationDe Novo Drug DesignLigand-based DesignMolecular Basis Of NeurodegenerationNeurodegenerative Disease PharmacologyNeurodegenerative DiseasesNeurodegenerative DisordersKinase Inhibitor Library DesignKinase Selectivity ProfilingLeucine Zipper ProteinsProperty-based Drug DesignProtein Kinase InhibitorsStructure-based De Novo Design
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.
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