Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors

J Med Chem. 2013 Jun 13;56(11):4521-36. doi: 10.1021/jm400266t. Epub 2013 May 29.

Abstract

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.

MeSH terms

  • 4-Aminopyridine / analogs & derivatives*
  • 4-Aminopyridine / chemical synthesis*
  • 4-Aminopyridine / pharmacokinetics
  • 4-Aminopyridine / pharmacology
  • Administration, Oral
  • Aminopyridines / chemical synthesis*
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / pharmacology
  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology
  • Biological Availability
  • Crystallography, X-Ray
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / metabolism
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 3 / antagonists & inhibitors
  • Mice
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Protein Binding
  • Rats
  • STAT4 Transcription Factor / antagonists & inhibitors
  • Stereoisomerism
  • Structure-Activity Relationship
  • TYK2 Kinase / antagonists & inhibitors*

Substances

  • 2-chloro-4-cyano-6-fluoro-N-(2-(2-fluorocyclopropanecarboxamido)pyridin-4-yl)benzamide
  • Aminopyridines
  • Benzamides
  • STAT4 Transcription Factor
  • Interleukin-12
  • Interferon-gamma
  • 4-Aminopyridine
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3
  • TYK2 Kinase

Associated data

  • PDB/4GI1
  • PDB/4GJ2
  • PDB/4GJ3