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The NADPH oxidase (Nox) family of enzymes plays a role in a variety of physiological and pathophysiological responses. Of particular interest is the Nox4 isoform which is widely distributed in various tissues including kidney, lung, liver, as well as heart and vasculature. Nox4 influences multiple biological functions by constitutively generating hydrogen peroxide. Recent literature strongly suggests that Nox4 contributes to disease development, such as, ischemia and fibrosis. The presentation describes our collaborative approach to rational drug development of Nox4 inhibitors. Our initial efforts were directed at the development of a pharmacophore model defining the structural characteristics necessary for Nox4 inhibition. These studies led to the identification of a tertiary sulfonylurea scaffold. A library of the sulfonylurea compounds was synthesized and screened for their NOX4 activity in vitro. One of the compounds in this library displayed potent Nox4 inhibitory activity (IC50 = 0.5 mM). Our current efforts are directed at refining the structure of our lead molecule and screening the biological activity of these compounds using in vivo models.
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