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[1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-17 , DOI: 10.1021/acs.jmedchem.9b01440 Elizabeth S Childress 1 , Joseph M Salamoun 1 , Stefan R Hargett 2 , Stephanie J Alexopoulos 3 , Sing-Young Chen 3 , Divya P Shah 3 , José Santiago-Rivera 1 , Christopher J Garcia 1 , Yumin Dai 1 , Simon P Tucker 4, 5 , Kyle L Hoehn 2, 3 , Webster L Santos 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-17 , DOI: 10.1021/acs.jmedchem.9b01440 Elizabeth S Childress 1 , Joseph M Salamoun 1 , Stefan R Hargett 2 , Stephanie J Alexopoulos 3 , Sing-Young Chen 3 , Divya P Shah 3 , José Santiago-Rivera 1 , Christopher J Garcia 1 , Yumin Dai 1 , Simon P Tucker 4, 5 , Kyle L Hoehn 2, 3 , Webster L Santos 1
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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 EC50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.
中文翻译：
[1,2,5]恶二唑[3,4-b]吡嗪-5,6-二胺衍生物作为线粒体解偶联剂，可用于非酒精性脂肪性肝炎的潜在治疗。
小分子线粒体解偶联剂正在作为治疗非酒精性脂肪性肝炎的一类新型分子出现。我们将BAM15（一种有效的质子体，可将线粒体解偶联而不使质膜去极化）用作结构活性分析的主要化合物。使用耗氧率作为测定解偶联活性的方法，介绍了恶二唑并吡嗪核心的5位和6位变化。我们的研究表明，与对称对应物相比，带有吸电子基团的非对称苯胺衍生物更为可取。另外，烷基取代基是不能容忍的，苯胺环的NH质子负责质子体的活性。特别地，化合物10b在L6成肌细胞中的EC 50值为190nM。在NASH的体内模型中，10b降低了肝甘油三酯水平，并显示出纤维化，炎症和血浆ALT的改善。综上所述，我们的研究表明线粒体解偶联剂具有治疗NASH的潜力。
更新日期：2020-02-17
中文翻译：
[1,2,5]恶二唑[3,4-b]吡嗪-5,6-二胺衍生物作为线粒体解偶联剂，可用于非酒精性脂肪性肝炎的潜在治疗。
小分子线粒体解偶联剂正在作为治疗非酒精性脂肪性肝炎的一类新型分子出现。我们将BAM15（一种有效的质子体，可将线粒体解偶联而不使质膜去极化）用作结构活性分析的主要化合物。使用耗氧率作为测定解偶联活性的方法，介绍了恶二唑并吡嗪核心的5位和6位变化。我们的研究表明，与对称对应物相比，带有吸电子基团的非对称苯胺衍生物更为可取。另外，烷基取代基是不能容忍的，苯胺环的NH质子负责质子体的活性。特别地，化合物10b在L6成肌细胞中的EC 50值为190nM。在NASH的体内模型中，10b降低了肝甘油三酯水平，并显示出纤维化，炎症和血浆ALT的改善。综上所述，我们的研究表明线粒体解偶联剂具有治疗NASH的潜力。
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