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

Publication date: Available online 17 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Qian Xu, Amol A. Kulkarni, Sajith Meleveetil, Dilbi Hussein, David Brown, Osman F. Güner, M. Damoder Reddy, E. Blake Watkins, Bernard Lassègue, Kathy K. Griendling, J. Phillip Bowen
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.

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