PLoS ONE (Jan 2020)

Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis.

  • Torsten Diesinger,
  • Vyacheslav Buko,
  • Alfred Lautwein,
  • Radovan Dvorsky,
  • Elena Belonovskaya,
  • Oksana Lukivskaya,
  • Elena Naruta,
  • Siarhei Kirko,
  • Viktor Andreev,
  • Dominik Buckert,
  • Sebastian Bergler,
  • Christian Renz,
  • Edith Schneider,
  • Florian Kuchenbauer,
  • Mukesh Kumar,
  • Cagatay Günes,
  • Berthold Büchele,
  • Thomas Simmet,
  • Dieter Müller-Enoch,
  • Thomas Wirth,
  • Thomas Haehner

DOI
https://doi.org/10.1371/journal.pone.0235990
Journal volume & issue
Vol. 15, no. 7
p. e0235990

Abstract

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Background and aimsAlcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH.MethodsIn this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies.ResultsA new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol.ConclusionsDue to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.