The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4500-4505. doi: 10.1016/j.bmcl.2017.07.072. Epub 2017 Aug 1.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.

Keywords: 2-Aminopyridines; Homology model; Kinativ; LRRK2; Parkinson’s.

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Animals
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Madin Darby Canine Kidney Cells / drug effects
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • alpha-aminopyridine