Triazolopyridazine LRRK2 kinase inhibitors

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 pot...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (7), p.1967-1973
Main Authors: Franzini, Maurizio, Ye, Xiaocong M., Adler, Marc, Aubele, Danielle L., Garofalo, Albert W., Gauby, Shawn, Goldbach, Erich, Probst, Gary D., Quinn, Kevin P., Santiago, Pam, Sham, Hing L., Tam, Danny, Truong, Anh, Ren, Zhao
Format: Article
Language:English
Subjects:
Activity
Binding mode
Bioisostere
chemistry
Discovery
Dose-Response Relationship, Drug
G2019S mutant
HEK293 Cells
Hinge
HTS
Humans
Inhibition
Kinase
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2
Models, Molecular
Molecular Structure
mutants
Oxidative metabolism
Parkinson disease
Parkinson’s
pathogenesis
Phosphorylation
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - metabolism
pyridazines
Pyridazines - chemical synthesis
Pyridazines - chemistry
Pyridazines - pharmacology
SAR
Selectivity
Structure-Activity Relationship
Synthesis
Treatment
Wild-type
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Description
Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.02.043