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

doi:10.1016/j.bmcl.2013.02.043

Triazolopyridazine LRRK2 kinase inhibitors

Bioorg Med Chem Lett. 2013 Apr 1;23(7):1967-73. doi: 10.1016/j.bmcl.2013.02.043. Epub 2013 Feb 14.

Authors

Maurizio Franzini¹, 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

Affiliation

¹ Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA. [email protected]

PMID: 23454015
DOI: 10.1016/j.bmcl.2013.02.043

Abstract

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.

MeSH terms

Dose-Response Relationship, Drug
HEK293 Cells
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Models, Molecular
Molecular Structure
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 / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyridazines
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Protein Serine-Threonine Kinases