Discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of LRRK2

Bioorg Med Chem Lett. 2013 Jul 15;23(14):4085-90. doi: 10.1016/j.bmcl.2013.05.054. Epub 2013 May 24.

Abstract

Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice.

MeSH terms

  • Animals
  • Brain / metabolism*
  • Cell Line
  • Drug Evaluation, Preclinical
  • Half-Life
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacokinetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Mutation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Indoles
  • Protein Kinase Inhibitors
  • indoline
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Protein Serine-Threonine Kinases