1. Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease.
- Author
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Yao CH, Shen ZQ, Rajan YC, Huang YW, Lin CY, Song JS, Shiao HY, Ke YY, Fan YS, Tsai CH, Yeh TK, Tsai TF, and Lee JC
- Subjects
- Animals, Mice, Down-Regulation, Hepatocytes metabolism, Liver metabolism, Thiophenes pharmacology, Thiophenes therapeutic use, Non-alcoholic Fatty Liver Disease drug therapy
- Abstract
Down-regulation of Cisd2 in the liver has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and increasing the level of Cisd2 is therefore a potential therapeutic approach to this group of diseases. Herein, we describe the design, synthesis, and biological evaluation of a series of Cisd2 activators, all thiophene analogs, based on a hit obtained using two-stage screening and prepared via either the Gewald reaction or by intramolecular aldol-type condensation of an N,S-acetal. Metabolic stability studies of the resulting potent Cisd2 activators suggest that thiophenes 4q and 6 are suitable for in vivo studies. The results from studies on 4q-treated and 6-treated Cisd2hKO-het mice, which carry a heterozygous hepatocyte-specific Cisd2 knockout, confirm that (1) there is a correlation between Cisd2 levels and NAFLD and (2) these compounds have the ability to prevent, without detectable toxicity, the development and progression of NAFLD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jinq-Chyi Lee and Ting-Fen Tsai reports financial support was provided by National Science and Technology Council. Jinq-Chyi Lee, Ting-Fen Tsai, Hui-Yi Shiao (Co-author) has patent #Methods of treating CDGSH iron sulfur domain 2 insufficiency associated disorders pending to Assignee: National Health Research Institutes, National Yang Ming Chiao Tung University, and Chang Gung Memorial Hospital, Linkou., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
- Published
- 2023
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