Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor

J Med Chem. 2015 Jan 8;58(1):419-32. doi: 10.1021/jm5014055. Epub 2014 Nov 17.

Abstract

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Area Under Curve
  • Brain / metabolism
  • Crystallography, X-Ray
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Mutation, Missense
  • Nitriles / chemistry
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology*
  • Parkinson Disease / drug therapy
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Proteome / antagonists & inhibitors*
  • Proteome / chemistry
  • Proteome / metabolism
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Rats

Substances

  • 3-(4-(morpholin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl)benzonitrile
  • Nitriles
  • Protein Kinase Inhibitors
  • Proteome
  • Pyrimidines
  • Pyrroles
  • benzonitrile
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases

Associated data

  • PDB/4U8Z
  • PDB/4W8D
  • PDB/4W8E