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

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

  • J Med Chem. 2019 Nov 27;62(22):10124-10143. doi: 10.1021/acs.jmedchem.9b00952.
Adeniyi Michael Adebesin 1,  Tim Wesser 2,  Jonnalagadda Vijaykumar 1,  Anne Konkel 2,  Mahesh P Paudyal 1,  Janine Lossie 2,  Chen Zhu 1,  Christina Westphal 3,  Narender Puli 1,  Robert Fischer 2,  Wolf-Hagen Schunck 3,  John R Falck 1
Affiliations

Affiliations

  • 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.
PMID: 31693857 DOI: 10.1021/acs.jmedchem.9b00952
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.

Figures
Products