دورية أكاديمية
Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice.
| العنوان: | Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice. |
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| المؤلفون: | Beretta M; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Dai Y; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA., Olzomer EM; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Vancuylenburg CS; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Santiago-Rivera JA; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA., Philp AM; St Vincent's Clinical School, UNSW Medicine, University of New South Wales, Sydney, New South Wales, Australia., Hargett SR; Department of Pharmacology, University of Virginia, Charlottesville, VA., Li K; Department of Pharmacology, University of Virginia, Charlottesville, VA., Shah DP; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Chen SY; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Alexopoulos SJ; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Li C; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Harris TE; Department of Pharmacology, University of Virginia, Charlottesville, VA., Lee B; Biological Resources Imaging Laboratory, University of New South Wales, Sydney, New South Wales, Australia., Wathier M; Life Biosciences, Boston, MA., Cermak JM; Life Biosciences, Boston, MA., Tucker SP; Life Biosciences, Boston, MA.; Firebrick Pharma, Melbourne, Victoria, Australia., Turner N; Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia., Bayliss DA; Department of Pharmacology, University of Virginia, Charlottesville, VA., Philp A; Centre for Healthy Ageing, Centenary Institute, Camperdown, New South Wales, Australia.; School of Sport, Exercise and Rehabilitation Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.; Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia., Byrne FL; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia., Santos WL; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA., Hoehn KL; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia.; Department of Pharmacology, University of Virginia, Charlottesville, VA. |
| المصدر: | Diabetes [Diabetes] 2024 Mar 01; Vol. 73 (3), pp. 374-384. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print Cited Medium: Internet ISSN: 1939-327X (Electronic) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Alexandria, VA : American Diabetes Association Original Publication: [New York, American Diabetes Association] |
| مواضيع طبية MeSH: | Glucose Intolerance*/drug therapy , Glucose Intolerance*/metabolism , Diabetes Mellitus, Type 2*/metabolism, Mice ; Rats ; Humans ; Animals ; Adiposity ; Obesity/etiology ; Liver/metabolism ; Diet, High-Fat/adverse effects ; Mice, Inbred C57BL |
| مستخلص: | 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. (© 2024 by the American Diabetes Association.) |
| التعليقات: | Comment in: Diabetes. 2024 Mar 1;73(3):357-358. (PMID: 38377448) |
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| معلومات مُعتمدة: | R01 DK128612 United States DK NIDDK NIH HHS; R25 GM072767 United States GM NIGMS NIH HHS; R01DK128612 United States RG CSR NIH HHS |
| تواريخ الأحداث: | Date Created: 20231023 Date Completed: 20240222 Latest Revision: 20240315 |
| رمز التحديث: | 20240315 |
| مُعرف محوري في PubMed: | PMC10882157 |
| DOI: | 10.2337/db23-0233 |
| PMID: | 37870907 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1939-327X |
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| DOI: | 10.2337/db23-0233 |