The development of CNS-active LRRK2 inhibitors using property-directed optimisation

Bioorg Med Chem Lett. 2013 Jul 1;23(13):3690-6. doi: 10.1016/j.bmcl.2013.04.086. Epub 2013 May 9.


Mutations in PARK8/LRRK2 are the most common genetic cause of Parkinson's disease. Inhibition of LRRK2 kinase activity has neuroprotective benefits, and provides a means of addressing the underlying biochemical cause of Parkinson's disease for the first time. Initial attempts to develop LRRK2 inhibitors were largely unsuccessful and highlight shortcomings intrinsic to traditional, high throughput screening methods of lead discovery. Recently, amino-pyrimidine GNE-7915 was reported as a potent (IC50=9 nM) selective (1/187 kinases), brain-penetrant and non-toxic inhibitor of LRRK2. The use of in silico modelling, extensive in vitro assays and resource-efficient in vivo techniques to produce GNE-7915, reflects a trend towards the concerted optimisation of potency, selectivity and pharmacokinetic properties in early-stage drug development.

MeSH terms

  • Central Nervous System / drug effects*
  • Central Nervous System / enzymology
  • Central Nervous System Agents / chemistry
  • Central Nervous System Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • High-Throughput Screening Assays
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Molecular Structure
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship


  • (4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone
  • Central Nervous System Agents
  • Morpholines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases