Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Kenwood, Brandon M.¹  Calderone, Joseph A.^2,3  Taddeo, Evan P.¹  Hoehn, Kyle L.^1,4,5,6,7  Santos, Webster L.^2,3 

[1] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA

[2] Virginia Tech, Dept Chem, Blacksburg, VA 24061 USA

[3] Virginia Tech, Virginia Tech Ctr Drug Discovery, Blacksburg, VA 24061 USA

[4] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA

[5] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA 22908 USA

[6] Univ Virginia, Emily Cour Clin Canc Ctr, Charlottesville, VA 22908 USA

[7] Univ New S Wales, Dept Biotechnol & Biomol Sci, Kensington, NSW 2052, Australia

关键词: Mitochondrial uncoupler;    Mitochondrial bioenergetics;    Protonophore;    Structure-activity relationships;    Pyrazines;   

DOI  :  10.1016/j.bmcl.2015.06.040

来源: Elsevier

【 摘 要 】

Chemical mitochondrial uncouplers are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. These uncouplers have potential for the treatment of diseases such as obesity, Parkinson's disease, and aging. We have previously identified a novel mitochondrial protonophore, named BAM15, which stimulates mitochondrial respiration across a broad dosing range compared to carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Herein, we report our investigations on the structure-activity relationship profile of BAM15. Our studies demonstrate the importance of the furazan, pyrazine, and aniline rings as well as pKa in maintaining its effective protonophore activity. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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