[1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis.
[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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DOI：
10.1021/acs.jmedchem.9b01440
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发表时间：
2020-03-12
影响因子：
7.3
通讯作者：
Santos WL
中科院分区：
文献类型：
--
作者：
Childress ES;Salamoun JM;Hargett SR;Alexopoulos SJ;Chen SY;Shah DP;Santiago-Rivera J;Garcia CJ;Dai Y;Tucker SP;Hoehn KL;Santos WL
小分子线粒体解偶联剂是治疗非酒精性脂肪性肝炎的一类新分子。我们利用BAM15作为结构-活性分析的先导化合物，BAM15是一种有效的质子载体，可以解偶而不使质膜去极化。用耗氧速率作为测定解偶联活性的指标，介绍了恶二唑吡嗪核心5位和6位的变化。我们的研究表明，与对称的苯胺衍生物相比，带有吸电子基团的不对称苯胺衍生物更受欢迎。此外，烷基取代基不耐受，苯胺环的N-H质子负责质子团活性。其中化合物10b对L6成肌细胞的EC50值为190 nM。在NASH的体内模型中，10b降低了肝脏甘油三酯水平，改善了纤维化、炎症和血浆ALT。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。
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.
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影响因子：
4.8
作者：
Chen W;Mook RA Jr;Premont RT;Wang J
通讯作者：
Wang J
影响因子：
5.5
作者：
Buckler, KJ;Vaughan-Jones, RD
通讯作者：
Vaughan-Jones, RD
DOI：
10.4103/1319-3767.173762
发表时间：
2016-01
期刊：
Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association
影响因子：
--
作者：
Alam S;Kabir J;Mustafa G;Gupta U;Hasan SK;Alam AK
通讯作者：
Alam AK
影响因子：
5.6
作者：
Berry BJ;Trewin AJ;Amitrano AM;Kim M;Wojtovich AP
通讯作者：
Wojtovich AP
影响因子：
3.4
作者：
Antonenko, Yuri N.;Denisov, Stepan S.;Kotova, Elena A.
通讯作者：
Kotova, Elena A.