The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2320-2326. doi: 10.1016/j.bmcl.2019.06.018. Epub 2019 Jun 17.

Abstract

The design, synthesis, and biological evaluation of novel 3-aryl-indazole derivatives as peripherally selective pan-Trk inhibitors are described. Three strategies were used to obtain a potent compound exhibiting low central nervous system (CNS) penetration and high plasma exposure: 1) a structure-based drug design (SBDD) approach was used to improve potency; 2) a substrate for an efflux transporter for lowering brain penetration was explored; and 3) the most basic pKa (pKa-MB) value was used as an indicator to identify compounds with good membrane permeability. This enabled the identification of the peripherally targeted 17c with the potency, kinase-selectivity, and plasma exposure required to demonstrate in vivo efficacy in a Complete Freund's adjuvant (CFA)-induced thermal hypersensitivity model.

Keywords: 3-Aryl-indazole derivative; Efflux transporter; Peripherally restricted; pKa-MB; pan-Trk inhibitor.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Indazoles / chemical synthesis
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Molecular Structure
  • Pain / drug therapy*
  • Pain / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Protein Kinase Inhibitors
  • Receptor Protein-Tyrosine Kinases