期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 7, 页码 1967-1973出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.02.043
关键词
LRRK2; Parkinson's; Inhibition; Kinase; Treatment; Discovery; Wild-type; G2019S mutant; Phosphorylation; SAR; Activity; Selectivity; Bioisostere; Hinge; HTS; Oxidative metabolism; Binding mode; Synthesis
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed. (C) 2013 Elsevier Ltd. All rights reserved.
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