title: Triazolopyridazine LRRK2 kinase inhibitors.
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.
authors: Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA. mauriziof@alumni.stanford.edu
authors: Maurizio
authors: M
authors: Franzini
authors: Xiaocong M
authors: XM
authors: Ye
authors: Marc
authors: M
authors: Adler
authors: Danielle L
authors: DL
authors: Aubele
authors: Albert W
authors: AW
authors: Garofalo
authors: Shawn
authors: S
authors: Gauby
authors: Erich
authors: E
authors: Goldbach
authors: Gary D
authors: GD
authors: Probst
authors: Kevin P
authors: KP
authors: Quinn
authors: Pam
authors: P
authors: Santiago
authors: Hing L
authors: HL
authors: Sham
authors: Danny
authors: D
authors: Tam
authors: Anh
authors: A
authors: Truong
authors: Zhao
authors: Z
authors: Ren
mesh_terms: D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases