Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4

Bioorg Med Chem. 2018 Mar 1;26(5):989-998. doi: 10.1016/j.bmc.2017.12.023. Epub 2017 Dec 17.

Abstract

NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, however, suggests that Nox4 plays a critical role in fibrosis, as well as a host of pathologies and diseases. These considerations led to a search for novel, small molecule inhibitors of this important enzyme. Ultimately, a series of novel tertiary sulfonylureas (23-25) was designed using pharmacophore modeling, synthesized, and evaluated for inhibition of Nox4-dependent signaling.

Keywords: Molecular modeling; NADPH oxidases; Nox4; Pharmacophore development; Reactive oxygen species (ROS).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Survival / drug effects
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • NADPH Oxidase 4 / antagonists & inhibitors*
  • NADPH Oxidase 4 / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Sulfonylurea Compounds / chemical synthesis
  • Sulfonylurea Compounds / chemistry*
  • Sulfonylurea Compounds / pharmacology

Substances

  • Enzyme Inhibitors
  • Reactive Oxygen Species
  • Sulfonylurea Compounds
  • NADPH Oxidase 4