Computer-Aided Selective Optimization of Side Activities of Talinolol

Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme solub...

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Published in:ACS medicinal chemistry letters 2019-06, Vol.10 (6), p.899-903
Main Authors: Hiesinger, Kerstin, Kramer, Jan S, Achenbach, Janosch, Moser, Daniel, Weber, Julia, Wittmann, Sandra K, Morisseau, Christophe, Angioni, Carlo, Geisslinger, Gerd, Kahnt, Astrid S, Kaiser, Astrid, Proschak, Anna, Steinhilber, Dieter, Pogoryelov, Denys, Wagner, Karen, Hammock, Bruce D, Proschak, Ewgenij
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Language:English
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Summary:Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure analysis of the sEH in complex with talinolol enables a straightforward optimization of inhibitory potency. The resulting lead structure exhibited in vivo activity in a rat model of diabetic neuropatic pain.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.9b00075