Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease.

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. Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Citation

Chun-Hsu Yao, Zhao-Qing Shen, Yesudoss Christu Rajan, Yu-Wen Huang, Chin-Yu Lin, Jen-Shin Song, Hui-Yi Shiao, Yi-Yu Ke, Yu-Shiou Fan, Chi-Hui Tsai, Teng-Kuang Yeh, Ting-Fen Tsai, Jinq-Chyi Lee. Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease. European journal of medicinal chemistry. 2023 Oct 05;258:115583

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PMID: 37393792

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