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Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice
Martina Beretta1, Yumin Dai2, Ellen M Olzomer1
1School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia.
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.
Insights
New drug candidate SHD865, an imidazolopyrazine mitochondrial uncoupler, effectively treats obesity and related metabolic disorders in mice. This compound shows promise for developing novel obesity therapies by increasing nutrient oxidation.
Area of Science:
- Biochemistry
- Pharmacology
- Metabolic Diseases
Background:
- Excess body fat is a major risk factor for metabolic diseases, contributing significantly to global morbidity and mortality.
- There is a critical need for effective treatments to manage obesity and its associated comorbidities like cardiovascular disease and type 2 diabetes.
- Pharmacologic mitochondrial uncouplers offer a potential therapeutic strategy for obesity by enhancing nutrient oxidation.
Purpose of the Study:
- To characterize a novel class of imidazolopyrazine mitochondrial uncouplers.
- To evaluate the in vitro and in vivo efficacy of compound SHD865, a derivative of BAM15, for treating obesity and related metabolic disorders.
Main Methods:
- In vitro and in vivo characterization of SHD865, a novel imidazolopyrazine mitochondrial uncoupler.
- Assessment of SHD865's effects on body composition, glucose tolerance, liver steatosis, and plasma lipid levels in a mouse model of diet-induced adiposity.
- Evaluation of SHD865's pharmacokinetic properties, including oral bioavailability and metabolic clearance.
Main Results:
- SHD865 demonstrated milder mitochondrial uncoupling than BAM15, with a lower maximal respiration rate.
- Six-week treatment with SHD865 in mice normalized body composition and glucose tolerance without affecting food intake.
- SHD865 treatment corrected liver steatosis and hyperlipidemia to levels comparable to control groups.
- SHD865 exhibited maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes.
Conclusions:
- Imidazolopyrazine mitochondrial uncouplers, exemplified by SHD865, represent a promising new class of drug candidates for managing obesity.
- SHD865 effectively reverses key metabolic abnormalities associated with obesity in preclinical models.
- These findings support the further development of SHD865 and related compounds for the treatment of obesity-related disorders.
