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

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- b ]pyridin-7-ol derivatives of BAM15. Utilizing an oxygen consumption rate assay as a measure of increased cellular respiration, SHO1122147 ( 7m ) displayed an EC ₅₀ of 3.6 μM in L6 myoblasts. Pharmacokinetic studies indicated a half-life of 2 h, C _max of 35 μM, and no observed adverse effects at 1,000 mg kg ^-1 dose in mice. In a Gubra-Amylin (GAN) mouse model of MASH, SHO1122147 was efficacious in decreasing body weight and liver triglyceride levels at 200 mg kg ^-1 day ^-1 without changes in body temperature. These findings indicate the potential of utilizing novel [1,2,5]oxadiazolo[3,4- b ]pyridin-7-ol mitochondrial uncouplers for treatment of fatty liver disease and obesity.