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Abstract
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis; and neuronal injury, such as chemotherapy induced peripheral neuropathy. Here we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.
Supplementary materials
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Supporting Information
Description
Experimental procedures; Kinase selectivity profile and Safety 87 profile for compound 59; Process chemistry route for compound 59 and single crystal X-ray diffraction data for key chiral intermediate in the synthesis of compound 59; X-ray data collection and refinement statistics for protein-ligand complexes using compounds 12 and 51
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Title
Spectral data
Description
1H NMR, LCMS and HPLC spectra for all compounds; SFC spectra for all chiral compounds
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