Novel cinnoline-based inhibitors of LRRK2 kinase activity

Bioorg Med Chem Lett. 2013 Jan 1;23(1):71-4. doi: 10.1016/j.bmcl.2012.11.021. Epub 2012 Nov 16.

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 cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / metabolism
  • Animals
  • Binding Sites
  • HEK293 Cells
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Molecular Docking Simulation
  • Mutation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Transfection

Substances

  • Amides
  • Heterocyclic Compounds, 2-Ring
  • Protein Kinase Inhibitors
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • cinnoline