Study summary · research use only
Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This mouse study examined SHD865, a liver-selective imidazolopyrazine mitochondrial uncoupler derived from the uncoupler BAM15, in a diet-induced adiposity model. In vitro, SHD865 was described as a milder uncoupler than BAM15, producing a lower maximal respiration rate. In vivo, 6-week treatment with SHD865 restored body composition and glucose tolerance to levels comparable with chow-fed control mice, without changing food intake, and corrected liver steatosis and plasma hyperlipidemia to levels comparable with controls. The compound was reported to have maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. The authors describe imidazolopyrazine mitochondrial uncouplers such as SHD865 as candidates for further drug development for obesity-related disorders.
Abstract
Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, 6-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls, without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders.
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