Design, Synthesis,\nand Biological Evaluation of [1,2,5]Oxadiazolo[3,4‑<i>b</i>]pyridin-7-ol as Mitochondrial Uncouplers for the Treatment\nof Obesity and Metabolic Dysfunction-Associated Steatohepatitis

Mitochondrial uncouplers are small molecule protonophores\nthat\nact to dissipate the proton motive force independent of adenosine\ntriphosphate (ATP) synthase. Mitochondrial uncouplers such as BAM15\nincrease respiration and energy expenditure and have potential in\ntreating a variety of metabolic diseases. In this study, we disclose\nthe structure–activity relationship profile of 6-substituted\n[1,2,5]oxadiazolo[3,4-<i>b</i>]pyridin-7-ol derivatives\nof BAM15. Utilizing an oxygen consumption rate assay as a measure\nof increased cellular respiration, <b>SHO1122147</b> (<b>7m</b>) displayed an EC<sub>50</sub> of 3.6 μM in L6 myoblasts.\nPharmacokinetic studies indicated a half-life of 2 h, <i>C</i><sub>max</sub> of 35 μM, and no observed adverse effects at\n1,000 mg kg<sup>–1</sup> dose in mice. In a Gubra-Amylin (GAN)\nmouse model of MASH, <b>SHO1122147</b> was efficacious in decreasing\nbody weight and liver triglyceride levels at 200 mg kg<sup>–1</sup> day<sup>–1</sup> without changes in body temperature. These\nfindings indicate the potential of utilizing novel [1,2,5]oxadiazolo[3,4-<i>b</i>]pyridin-7-ol mitochondrial uncouplers for treatment of\nfatty liver disease and obesity.