Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffold

Article ID	Journal	Published Year	Pages	File Type
10590954	Bioorganic & Medicinal Chemistry Letters	2014	9 Pages	PDF

Abstract

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.

Keywords

ROC COR LRRK2 CSD HLM Bcrp KSS MDR1 LRR PDB ARM ANK HTS SAR WCA WD40 Brain impairment armadillo repeat domain AUC MPO PK/PD Ankyrin repeat domain Multi-parameter optimization Alzheimer’s disease Parkinson’s disease CNS Structure activity relationship blood brain barrier BBB central nervous system high throughput screening Pharmacokinetic/pharmacodynamic LIPE Genome-wide association studies GWAS area under the curve Kinase inhibitors human liver microsome knockout efflux ratio wild type Cambridge structural database Protein Data Bank Ligand efficiency lipophilic ligand efficiency leucine rich repeat kinase 2

Related Topics

Physical Sciences and Engineering Chemistry Organic Chemistry

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Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffold

Authors

Paul Galatsis, Jaclyn L. Henderson, Bethany L. Kormos, Seungil Han, Ravi G. Kurumbail, Travis T. Wager, Patrick R. Verhoest, G. Stephen Noell, Yi Chen, Elie Needle, Zdenek Berger, Stefanus J. Steyn, Christopher Houle, Warren D. Hirst,