Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4370-4376. doi: 10.1016/j.bmcl.2017.08.022. Epub 2017 Aug 12.

Abstract

Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.

Keywords: IL-23; Imidazopyridine; Kinase; Psoriasis; TYK2.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • TYK2 Kinase / antagonists & inhibitors*
  • TYK2 Kinase / metabolism

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • imidazopyridine
  • TYK2 Kinase
  • TYK2 protein, human