Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases

J Med Chem. 2018 Feb 8;61(3):1130-1152. doi: 10.1021/acs.jmedchem.7b01598. Epub 2018 Jan 23.

Abstract

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy
  • Autoimmune Diseases / drug therapy*
  • Cyclobutanes / chemistry
  • Cyclobutanes / pharmacokinetics
  • Cyclobutanes / pharmacology*
  • Cyclobutanes / therapeutic use
  • Dogs
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / chemistry
  • Janus Kinase 2 / antagonists & inhibitors
  • Models, Molecular
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Pyrroles / chemistry
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Pyrroles / therapeutic use
  • Rats
  • Substrate Specificity
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Tissue Distribution

Substances

  • Cyclobutanes
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Sulfonamides
  • Janus Kinase 1
  • Janus Kinase 2