Triazolopyridazine LRRK2 kinase inhibitors.

Maurizio Franzini,Xiaocong M Ye,Marc Adler,Danielle L Aubele,Albert W Garofalo,Shawn Gauby,Erich Goldbach,Gary D Probst,Kevin P Quinn,Pam Santiago,Hing L Sham,Danny Tam,Anh Truong,Zhao Ren

Bioorganic & Medicinal Chemistry Letters（2013）

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摘要

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.

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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

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