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

Autor: Berthold Büchele, Elena Belonovskaya, Cagatay Günes, Oksana Lukivskaya, Florian Kuchenbauer, Siarhei Kirko, Thomas Wirth, Thomas Simmet, Edith Schneider, Dominik Buckert, Radovan Dvorsky, Alfred Lautwein, Dieter Müller-Enoch, Viktor Andreev, Sebastian Bergler, Vyacheslav Buko, Thomas Haehner, Christian Renz, Torsten Diesinger, Elena Naruta, Mukesh Kumar
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Alcoholic liver disease
Alcoholic Liver Disease
Pharmacology
Lipoproteins
VLDL
Severity of Illness Index
Biochemistry
0302 clinical medicine
Medicine and Health Sciences
030212 general & internal medicine
media_common
Multidisciplinary
Alcohol Consumption
Drug discovery
Organic Compounds
Pharmaceutics
Liver Diseases
Fatty liver
Ursodeoxycholic Acid
Cytochrome P-450 CYP2E1
Hep G2 Cells
CYP2E1
Lipids
Ursodeoxycholic acid
Cytochrome P-450 CYP2E1 Inhibitors
Chemistry
Liver
Physical Sciences
Medicine
030211 gastroenterology & hepatology
Female
medicine.drug
Fatty Liver
Alcoholic
Research Article
Drug
media_common.quotation_subject
Science
Drug design
Gastroenterology and Hepatology
03 medical and health sciences
Drug Therapy
Alkanes
medicine
Animals
Humans
Rats
Wistar
Imidazole
Triglycerides
Nutrition
Ethanol
business.industry
Organic Chemistry
Chemical Compounds
Correction
Biology and Life Sciences
medicine.disease
Rats
Diet
Fatty Liver
Oxidative Stress
Targeted drug delivery
Alcohols
business
Reactive Oxygen Species
Zdroj: PLoS ONE
PLoS ONE, Vol 15, Iss 7, p e0235990 (2020)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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