TY - JOUR
T1 - Development of Robust 17(R),18(S)-Epoxyeicosatetraenoic Acid (17,18-EEQ) Analogues as Potential Clinical Antiarrhythmic Agents
AU - Adebesin, Adeniyi Michael
AU - Wesser, Tim
AU - Vijaykumar, Jonnalagadda
AU - Konkel, Anne
AU - Paudyal, Mahesh P.
AU - Lossie, Janine
AU - Zhu, Chen
AU - Westphal, Christina
AU - Puli, Narender
AU - Fischer, Robert
AU - Schunck, Wolf Hagen
AU - Falck, John R.
N1 - Funding Information:
Financial support was provided by the Robert A. Welch Foundation (I-0011) and the Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG) to W.-H.S. (FOR 1054; SCHU 822/5 and FOR1368; SCHU822/7).
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/11/27
Y1 - 2019/11/27
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.9b00952
DO - 10.1021/acs.jmedchem.9b00952
M3 - Article
C2 - 31693857
AN - SCOPUS:85075584383
SN - 0022-2623
VL - 62
SP - 10124
EP - 10143
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -