Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

J Med Chem. 2017 Jan 26;60(2):767-786. doi: 10.1021/acs.jmedchem.6b01634. Epub 2017 Jan 4.

Abstract

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Cutaneous
  • Administration, Inhalation
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / toxicity
  • Binding Sites
  • Crystallography, X-Ray
  • Dogs
  • Drug Design
  • Hepatocytes / metabolism
  • Heterocyclic Compounds, 2-Ring / administration & dosage
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Heterocyclic Compounds, 2-Ring / toxicity
  • Humans
  • Indazoles / administration & dosage
  • Indazoles / chemical synthesis
  • Indazoles / pharmacology*
  • Indazoles / toxicity
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 3 / antagonists & inhibitors
  • Janus Kinases / antagonists & inhibitors*
  • Lung Diseases / drug therapy*
  • Mice, Inbred BALB C
  • Microsomes, Liver / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / toxicity
  • Rats
  • Skin Diseases / drug therapy*
  • Solubility

Substances

  • Anti-Inflammatory Agents
  • Heterocyclic Compounds, 2-Ring
  • Indazoles
  • PF-06263276
  • Protein Kinase Inhibitors
  • JAK1 protein, human
  • JAK2 protein, human
  • JAK3 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3
  • Janus Kinases