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

• Type of Material: Article
• Authors: Qian Xu, Emory University; Amol A. Kulkarni, Howard University; Sajith Meleveetil, Howard University; Dilbi Hussein, Howard University; David Brown, Emory University; Osman F. Guner, Mercer University; M. Damoder Reddy, Union University; E. Blake Watkins, Union University; Bernard Lassegue, Emory University; Kathy Griendling, Emory University; J. Phillip Bowen, Mercer University
• Language: English
• Date: 2018-03-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmc.2017.12.023
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry
• ISSN: 0968-0896
• Volume: 26
• Issue: 5
• Start Page: 989
• End Page: 998
• Grant/Funding Information: This research was partially funded by Union University.; The authors are grateful for the HRESMS data provided by D. R. Phillips and C.-W. Chou [Proteomics and Mass Spectrometry (PAMS) Facility, NIH grant 1S10RR1028859] at the University of Georgia, Department of Chemistry, Athens, Georgia.
• Keywords: HYPERTROPHY; NAD(P)H OXIDASE; Reactive oxygen species (ROS); OXIDATIVE STRESS; HYPERTENSION; Molecular modeling; Nox4; Chemistry, Medicinal; Chemistry; EXPRESSION; SUPEROXIDE; Physical Sciences; NADPH oxidases; IN-VIVO; KIDNEY; Pharmacophore development; THERAPEUTIC TARGETS; Science & Technology; Biochemistry & Molecular Biology; Chemistry, Organic; Life Sciences & Biomedicine; DIABETIC-NEPHROPATHY; Pharmacology & Pharmacy
• Research Categories: Biology, Molecular; Chemistry, Organic; Chemistry, Pharmaceutical

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.