Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N‑(1H‑Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)
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 favor...
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Veröffentlicht in: | Journal of medicinal chemistry 2015-10, Vol.58 (20), p.8182-8199 |
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Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/acs.jmedchem.5b01072 |