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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of medicinal chemistry 2015-10, Vol.58 (20), p.8182-8199
Hauptverfasser: Patel, Snahel, Harris, Seth F, Gibbons, Paul, Deshmukh, Gauri, Gustafson, Amy, Kellar, Terry, Lin, Han, Liu, Xingrong, Liu, Yanzhou, Liu, Yichin, Ma, Changyou, Scearce-Levie, Kimberly, Ghosh, Arundhati Sengupta, Shin, Young G, Solanoy, Hilda, Wang, Jian, Wang, Bei, Yin, Jianping, Siu, Michael, Lewcock, Joseph W
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01072