Small molecule mitochondrial uncouplers have recently garnered great interest for their potential in treating nonalcoholic steatohepatitis (NASH). In this study, we report the structure–activity relationship profiling of a 6-amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol core, which utilizes the hydroxy moiety as the proton transporter across the mitochondrial inner membrane. We demonstrate that a wide array of substituents is tolerated with this novel scaffold that increased cellular metabolic rates in vitro using changes in oxygen consumption rate as a readout. In particular, compound SHS4121705 (12i) displayed an EC₅₀ of 4.3 μM in L6 myoblast cells and excellent oral bioavailability and liver exposure in mice. In the STAM mouse model of NASH, administration of 12i at 25 mg kg^–1 day^–1 lowered liver triglyceride levels and improved liver markers such as alanine aminotransferase, NAFLD activity score, and fibrosis. Importantly, no changes in body temperature or food intake were observed. As potential treatment of NASH, mitochondrial uncouplers show promise for future development.

中文翻译：

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在非酒精性脂肪性肝炎STAM小鼠模型中，作为有效线粒体解偶联剂的6-氨基[1,2,5]恶二唑并[3,4-b]吡嗪-5-ol衍生物。

小分子线粒体解偶联剂最近在治疗非酒精性脂肪性肝炎（NASH）中的潜力引起了极大的兴趣。在这项研究中，我们报告了6-氨基[1,2,5]恶二唑并[3,4- b ]吡嗪-5-醇核的结构-活性关系图谱，该图谱利用羟基作为质子转运蛋白。线粒体内膜。我们证明了这种新颖的支架可以耐受各种各样的取代基，该支架使用氧气消耗率的变化作为读数提高体外细胞代谢率。尤其是化合物SHS4121705（12i）的EC ₅₀L6成肌细胞中含有4.3μM的脂质，小鼠具有出色的口服生物利用度和肝脏暴露。在NASH的STAM小鼠模型中，以25 mg kg ^–1天^–1的剂量施用12i降低了肝脏甘油三酯水平，并改善了肝标志物，如丙氨酸转氨酶，NAFLD活性评分和纤维化。重要的是，没有观察到体温或食物摄入量的变化。线粒体解偶联剂作为NASH的潜在治疗方法，对未来的发展显示出希望。