Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31, A-8010 Graz, Austria; BIOTECHMED Graz, A-8010, Austria.
Bioorg Med Chem. 2020 Aug 15;28(16):115610. doi: 10.1016/j.bmc.2020.115610. Epub 2020 Jul 4.
High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.
血清中脂肪酸（FA）水平升高与胰岛素抵抗的发生有因果关系，胰岛素抵抗最终会发展为 2 型糖尿病和非酒精性脂肪肝（NAFLD），这两种疾病通常被归为代谢综合征。脂肪甘油三酯脂肪酶（ATGL）是水解细胞内甘油三酯（TG）储存的初始酶，将脂肪酸从脂肪细胞释放到血液循环中。因此，ATGL 特异性抑制剂有可能降低循环 FA 浓度，并抵抗胰岛素抵抗和 NAFLD 的发展。在本文中，我们报告了关于鼠 ATGL 小分子抑制剂的结构-活性关系（SAR）研究，该研究导致了 Atglistatin 的开发。Atglistatin 是鼠 ATGL 的特异性抑制剂，已被证明对验证 ATGL 作为潜在药物靶点非常有用。
