Development of robust 17(R),18(S)-epoxyeicosatetraenoic acid (17,18-EEQ) analogues as potential clinical antiarrhythmic agents

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Item Type:	Article
Title:	Development of robust 17(R),18(S)-epoxyeicosatetraenoic acid (17,18-EEQ) analogues as potential clinical antiarrhythmic agents
Creators Name:	Adebesin, A.M., Wesser, T., Vijaykumar, J., Konkel, A., Paudyal, M., Lossie, J., Zhu, C., Westphal, C., Puli, N., Fischer, R., Schunck, W.H. and Falck, J.
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.
Keywords:	Anti-Arrhythmia Agents, Arachidonic Acids, Cardiac Myocytes, Drug Dose-Response Relationship, Drug Stability, Epoxide Hydrolases, Esterification, Hepatocytes, Liver Microsomes, Myocardial Infarction, Oral Administration, Sprague-Dawley Rats, Wistar Rats, Animals, Mice, Rats
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society
Volume:	62
Number:	22
Page Range:	10124-10143
Date:	27 November 2019
Official Publication:	https://doi.org/10.1021/acs.jmedchem.9b00952
PubMed:	View item in PubMed

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