RT Journal Article
SR Electronic
T1 ω-imidazolyl-alkyl derivatives as new preclinical drug candidates for NASH therapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 685115
DO 10.1101/685115
A1 Torsten Diesinger
A1 Alfred Lautwein
A1 Vyacheslav Buko
A1 Elena Belonovskaya
A1 Oksana Lukivskaya
A1 Elena Naruta
A1 Siarhei Kirko
A1 Viktor Andreev
A1 Radovan Dvorsky
A1 Dominik Buckert
A1 Sebastian Bergler
A1 Christian Renz
A1 Dieter Müller-Enoch
A1 Thomas Wirth
A1 Thomas Haehner
YR 2019
UL http://biorxiv.org/content/early/2019/06/28/685115.abstract
AB Cytochrome P450 2E1 (CYP2E1) and its production of ROS play an essential role in the development and progression of inflammatory liver diseases such as alcoholic steatohepatitis. For this isoenzyme we have developed two new inhibitors - 12-imidazolyl-1-dodecanol (I-ol) and 1-imidazolyldodecane (I-an) - and wanted to test their effect on the related disease of non-alcoholic steatohepatitis (NASH). The fat-rich Lieber-DeCarli diet, which was administered over the entire experimental period of 16 weeks, was used for disease induction in the rat model, while the experimental substances were administered in parallel over the last four weeks. This high-calorie diet pathologically altered the ROS balance, the amount of adipocytokines, TNF-α and lipids as well as the activities of liver enzymes. Together with the histological examinations, the conclusion could be drawn that the diet led to the formation of NASH. I-ol and to a lesser extent I-an were able to shift the pathological values towards the normal range - despite continued administration of the noxious agent. I-ol, in particular, showed an extremely good tolerability in the acute toxicity study in rats. Thus, CYP2E1 appears to be a suitable drug target as well as I-ol and I-an promising drug candidates for the treatment of NASH.