First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis

J Med Chem. 2010 Nov 11;53(21):7715-30. doi: 10.1021/jm100773e.


We describe the design, synthesis, and optimization of first-in-class series of inhibitors of NADPH oxidase isoform 4 (Nox4), an enzyme implicated in several pathologies, in particular idiopathic pulmonary fibrosis, a life-threatening and orphan disease. Initially, several moderately potent pyrazolopyridine dione derivatives were found during a high-throughput screening campaign. SAR investigation around the pyrazolopyridine dione core led to the discovery of several double-digit nanomolar inhibitors in cell free assays of reactive oxygen species (ROS) production, showing high potency on Nox4 and Nox1. The compounds have little affinity for Nox2 isoform and are selective for Nox4/1 isoforms. The specificity of these compounds was confirmed in an extensive in vitro pharmacological profile, as well as in a counterscreening assay for potential ROS scavenging. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo, allowing further clinical trials for the potential treatment of fibrotic diseases, cancers, and cardiovascular and metabolic diseases.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Cell Line
  • Chronic Disease
  • Cricetinae
  • Cricetulus
  • Free Radical Scavengers / chemical synthesis
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Kidney Diseases / drug therapy
  • Male
  • Microsomes, Liver / metabolism
  • NADPH Oxidase 4
  • NADPH Oxidases / antagonists & inhibitors*
  • Pulmonary Fibrosis / drug therapy*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship


  • Free Radical Scavengers
  • Isoenzymes
  • Pyrazoles
  • Pyridines
  • Reactive Oxygen Species
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX4 protein, human