title: 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).
abstract: 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.
authors.forename: Snahel
authors.initials: S
authors.lastname: Patel
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.forename: Terry
authors.initials: T
authors.lastname: Kellar
authors.forename: Han
authors.initials: H
authors.lastname: Lin
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Liu
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemistry, WuXi AppTec Co., Ltd. , 288 Fute Zhonglu, Wai Gao Qiao Free Trade Zone, Shanghai, 200131, P. R. China.
authors.forename: Changyou
authors.initials: C
authors.lastname: Ma
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Arundhati Sengupta
authors.initials: AS
authors.lastname: Ghosh
authors.forename: Young G
authors.initials: YG
authors.lastname: Shin
authors.forename: Hilda
authors.initials: H
authors.lastname: Solanoy
authors.affiliation: Department of Chemistry, WuXi AppTec Co., Ltd. , 288 Fute Zhonglu, Wai Gao Qiao Free Trade Zone, Shanghai, 200131, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Jianping
authors.initials: J
authors.lastname: Yin
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lewcock
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12; D048670:MAP Kinase Kinase 4