Interest in mitochondrial uncoupling as potential therapeutics for metabolic diseases is rapidly growing. Small lipophilic molecules that can shuttle protons across the mitochondrial inner membrane can trigger an increase in metabolic rates within cells. This modulation of metabolic rate demonstrated a beneficial effect in animal models of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD), ischemia-reperfusion injury, and neurodegenerative diseases. We recently used BAM15 as a prototype mitochondrial uncoupler to demonstrate prevention and reversal of diet-induced obesity in mice. In this study, we will discuss the development of 6-amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol derivatives as potent mitochondrial uncouplers. In particular, compound SHS4121705 has excellent oral bioavailability with a half-life of 5.7 h and EC50 of 4.3 μM in L6 myoblast cells. In the STAM mouse model of nonalcoholic steatohepatitis (NASH), oral dosing of SHS4121705 at 25 mg kg−1 day−1 resulted in an improvement in liver biochemical markers and a 2-point reduction in NAFLD activity score (including reduction in steatosis, inflammation, and ballooning). SHS4121705 did not alter food intake or body temperature. These advancements reinforce the promise of mitochondrial uncouplers as potential therapeutics.

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol derivatives as novel mitochondrial uncouplers efficacious in mouse models of nonalcoholic steatohepatitis

ACS Fall 2021

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