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J Med Chem. 2019 Nov 27;62(22):10124-10143. doi: 10.1021/acs.jmedchem.9b00952. Epub 2019 Nov 19.

Development of Robust 17(R),18(S)-Epoxyeicosatetraenoic Acid (17,18-EEQ) Analogues as Potential Clinical Antiarrhythmic Agents.

Author information

1
Division of Chemistry, Department of Biochemistry , University of Texas Southwestern , Dallas , Texas 75390 , United States.
2
OMEICOS Therapeutics GmbH , Robert-Rössle-Straße 10 , 13125 Berlin , Germany.
3
Max Delbrück Center for Molecular Medicine , Robert-Rössle-Straße 10 , 13125 Berlin , Germany.

Abstract

17(R),18(S)-Epoxyeicosatetraenoic acid (EEQ) is a cytochrome P450 metabolite of eicosapentaenoic acid (EPA) and a powerful negative chronotrope with low nanomolar activity in a neonatal rat cardiomyocyte (NRCM) arrhythmia model. Prior studies identified oxamide 2b as a soluble epoxide hydrolase (sEH) stable replacement but unsuitable for in vivo applications due to limited oral bioavailability and metabolic stability. These ADME limitations have been addressed in an improved generation of negative chronotropes, e.g., 4 and 16, which were evaluated as potential clinical candidates.

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