[1,2,5]恶二唑并[3,4 -]吡啶 - 7 - 醇作为线粒体解偶联剂用于治疗肥胖症和代谢功能障碍相关脂肪性肝炎的设计、合成及生物学评价 - Suppr

Design, Synthesis, and Biological Evaluation of [1,2,5]Oxadiazolo[3,4-]pyridin-7-ol as Mitochondrial Uncouplers for the Treatment of Obesity and Metabolic Dysfunction-Associated Steatohepatitis.

作者信息

Foutz Mary A, Krinos Emily L, Beretta Martina, Hargett Stefan R, Shrestha Riya, Murray Jacob H, Duerre Ethan, Salamoun Joseph M, McCarter Katrina, Shah Divya P, Hoehn Kyle L, Santos Webster L

机构信息

Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia.

出版信息

J Med Chem. 2024 Dec 12;67(23):21486-21504. doi: 10.1021/acs.jmedchem.4c02366. Epub 2024 Nov 30.

Mitochondrial uncouplers are small molecule protonophores that act to dissipate the proton motive force independent of adenosine triphosphate (ATP) synthase. Mitochondrial uncouplers such as BAM15 increase respiration and energy expenditure and have potential in treating a variety of metabolic diseases. In this study, we disclose the structure-activity relationship profile of 6-substituted [1,2,5]oxadiazolo[3,4-]pyridin-7-ol derivatives of BAM15. Utilizing an oxygen consumption rate assay as a measure of increased cellular respiration, () displayed an EC of 3.6 μM in L6 myoblasts. Pharmacokinetic studies indicated a half-life of 2 h, of 35 μM, and no observed adverse effects at 1,000 mg kg dose in mice. In a Gubra-Amylin (GAN) mouse model of MASH, was efficacious in decreasing body weight and liver triglyceride levels at 200 mg kg day without changes in body temperature. These findings indicate the potential of utilizing novel [1,2,5]oxadiazolo[3,4-]pyridin-7-ol mitochondrial uncouplers for treatment of fatty liver disease and obesity.

线粒体解偶联剂是小分子质子载体，其作用是独立于三磷酸腺苷（ATP）合酶来耗散质子动力。诸如BAM15之类的线粒体解偶联剂可增加呼吸作用和能量消耗，并在治疗多种代谢疾病方面具有潜力。在本研究中，我们揭示了BAM15的6-取代[1,2,5]恶二唑并[3,4-b]吡啶-7-醇衍生物的构效关系概况。利用耗氧率测定作为细胞呼吸增加的量度，（此处原文括号内容缺失具体化合物信息，无法准确翻译）在L6成肌细胞中显示出3.6 μM的半数有效浓度（EC）。药代动力学研究表明，其半衰期为2小时，血浆峰浓度（Cmax）为35 μM，在小鼠1000 mg/kg剂量下未观察到不良反应。在马什氏脂肪性肝炎（MASH）的古布拉-胰淀素（GAN）小鼠模型中，（此处原文括号内容缺失具体化合物信息，无法准确翻译）在200 mg/kg/天的剂量下可有效降低体重和肝脏甘油三酯水平，且体温无变化。这些发现表明利用新型[1,2,5]恶二唑并[3,4-b]吡啶-7-醇线粒体解偶联剂治疗脂肪肝疾病和肥胖症的潜力。