Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors

Bioorg Med Chem Lett. 2013 Apr 1;23(7):1974-7. doi: 10.1016/j.bmcl.2013.02.041. Epub 2013 Feb 15.

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Quinolines
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Protein Serine-Threonine Kinases