دورية أكاديمية
[1,2,5]Oxadiazolo[3,4- b ]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis.
| العنوان: | [1,2,5]Oxadiazolo[3,4- b ]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis. |
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| المؤلفون: | Childress ES; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States., Salamoun JM; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States., Hargett SR; Departments of Pharmacology and Medicine, University of Virginia, Charlottesville, Virginia 22908, United States., Alexopoulos SJ; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia., Chen SY; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia., Shah DP; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia., Santiago-Rivera J; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States., Garcia CJ; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States., Dai Y; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States., Tucker SP; Continuum Biosciences, Pty Ltd., 2035 Sydney, Australia.; Continuum Biosciences Inc., Boston, Massachusetts 02116, United States., Hoehn KL; Departments of Pharmacology and Medicine, University of Virginia, Charlottesville, Virginia 22908, United States.; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia., Santos WL; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2020 Mar 12; Vol. 63 (5), pp. 2511-2526. Date of Electronic Publication: 2020 Feb 17. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Diamines/*therapeutic use , Mitochondria, Liver/*drug effects , Non-alcoholic Fatty Liver Disease/*drug therapy , Pyrazines/*therapeutic use , Uncoupling Agents/*therapeutic use, Animals ; Diamines/chemistry ; Diamines/pharmacology ; Liver/drug effects ; Liver/metabolism ; Male ; Mice, Inbred C57BL ; Mitochondria, Liver/metabolism ; Non-alcoholic Fatty Liver Disease/metabolism ; Oxadiazoles/chemistry ; Oxadiazoles/pharmacology ; Oxadiazoles/therapeutic use ; Oxygen Consumption/drug effects ; Pyrazines/chemistry ; Pyrazines/pharmacology ; Uncoupling Agents/chemistry ; Uncoupling Agents/pharmacology |
| مستخلص: | Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure-activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N-H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC |
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| معلومات مُعتمدة: | R25 GM072767 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (Diamines) 0 (Oxadiazoles) 0 (Pyrazines) 0 (Uncoupling Agents) |
| تواريخ الأحداث: | Date Created: 20200205 Date Completed: 20200831 Latest Revision: 20210626 |
| رمز التحديث: | 20240829 |
| مُعرف محوري في PubMed: | PMC8224984 |
| DOI: | 10.1021/acs.jmedchem.9b01440 |
| PMID: | 32017849 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.9b01440 |