Design,synthesis, and biological evaluation of inhibitors of the NADPH oxidase,Nox4 |
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| Authors: | Qian Xu Amol A Kulkarni Ayyiliath M Sajith Dilbi Hussein David Brown Osman F Güner M Damoder Reddy E Blake Watkins Bernard Lassègue Kathy K Griendling J Phillip Bowen |
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| Institution: | 1. Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA 30322, USA;2. Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC 20059, USA;3. Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA;4. Department of Pharmaceutical Sciences, College of Pharmacy, Union University, Jackson, TN 38305, USA;5. Current address: Department of Chemistry and Physics, Santa Rosa Junior College, Santa Rosa, CA 95401, USA |
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| 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. |
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| Keywords: | NADPH oxidases Nox4 Reactive oxygen species (ROS) Pharmacophore development Molecular modeling |
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