Discovery of 5-substituent-N-arylbenzamide derivatives as potent, selective and orally bioavailable LRRK2 inhibitors

Bioorg Med Chem Lett. 2017 Sep 1;27(17):4034-4038. doi: 10.1016/j.bmcl.2017.07.052. Epub 2017 Jul 21.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.

Keywords: Arylbenzamide; CNS penetration; Kinase selectivity; LRRK2 inhibitor; Parkinson’s disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Benzamides / administration & dosage
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

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