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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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (7), p.1967-1973
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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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Zusammenfassung:	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