Study summary · research use only
[1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This medicinal chemistry study (species not specified for the in vivo portion) evaluated oxadiazolopyrazine derivatives of the mitochondrial uncoupler BAM15 for potential use in nonalcoholic steatohepatitis (NASH). Using oxygen consumption rate assays, the authors describe structure-activity relationships, noting unsymmetrical aniline derivatives with electron-withdrawing groups over symmetrical ones, and that alkyl substituents were not tolerated. Compound 10b had an EC50 of 190 nM in L6 myoblast cells. In an in vivo NASH model, 10b was reported to decrease liver triglyceride levels and was associated with changes in fibrosis, inflammation, and plasma ALT measures.
Abstract
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.
pepmg summarizes the peer-reviewed literature and links to every source — it sells nothing, ships nothing, and gives no medical, dosing, or human-use guidance. Don't just trust this summary: follow the citation to its source and read it yourself. Research use only.