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ACS Med Chem Lett. 2019 May 29;10(6):899-903. doi: 10.1021/acsmedchemlett.9b00075. eCollection 2019 Jun 13.

Computer-Aided Selective Optimization of Side Activities of Talinolol.

Author information

1
Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Strasse 9, D-60438 Frankfurt am Main, Germany.
2
Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, One Shields Avenue, Davis, California 95616, United States.
3
Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, ZAFES, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
4
Branch for Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
5
Institute of Biochemistry, Goethe-University of Frankfurt, Max-von-Laue Strasse 9, D-60438 Frankfurt am Main, Germany.

Abstract

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.

PMID:
31223445
PMCID:
PMC6580380
[Available on 2020-06-13]
DOI:
10.1021/acsmedchemlett.9b00075

Conflict of interest statement

The authors declare no competing financial interest.

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