5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy

Bioorg Med Chem Lett. 2019 Jan 15;29(2):212-215. doi: 10.1016/j.bmcl.2018.11.054. Epub 2018 Nov 28.

Abstract

We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.

Keywords: CNS penetration; LRRK2; PFI; Parkinson’s disease; Unbound fraction.

MeSH terms

  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Brain / drug effects*
  • Brain / metabolism
  • Dose-Response Relationship, Drug
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Protein Kinase Inhibitors
  • Pyridazines
  • pyridazine
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2