Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
Departments of Pharmacology and Medicine, University of Virginia, Charlottesville, Virginia 22908, United States.
J Med Chem. 2020 Mar 12;63(5):2511-2526. doi: 10.1021/acs.jmedchem.9b01440. Epub 2020 Feb 17.
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 had an EC value of 190 nM in L6 myoblast cells. In an model of NASH, 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.
小分子线粒体解偶联剂作为一类新兴的治疗非酒精性脂肪性肝炎的分子正在出现。我们利用 BAM15（一种有效的质子载体，可解耦线粒体而不会去极化质膜）作为结构活性分析的先导化合物。我们使用耗氧量作为测定解偶联活性的测定方法，在噁二唑并吡嗪核心的 5-和 6-位引入了变化。我们的研究表明，与对称物相比，带有吸电子基团的不对称苯胺衍生物更受青睐。此外，烷基取代基不能耐受，苯胺环的 N-H 质子负责质子载体活性。特别是，化合物在 L6 成肌细胞中的 EC 值为 190 nM。在 NASH 的模型中， 降低了肝甘油三酯水平，并显示纤维化、炎症和血浆 ALT 得到改善。总之，我们的研究表明，线粒体解偶联剂具有治疗 NASH 的潜力。
