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Triazolopyridazine LRRK2 kinase inhibitors

2013; Elsevier BV; Volume: 23; Issue: 7 Linguagem: Inglês

10.1016/j.bmcl.2013.02.043

1464-3405

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, Vy Anh Truong, Zhao Ren,

Signaling Pathways in Disease

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.