Quinlan Joseph E, Salamoun Joseph M, Garcia Christopher J, Hargett Stefan, Beretta Martina, Shrestha Riya, Li Catherine, Hoehn Kyle L, Santos Webster L
Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24060, United States.
Department of Pharmacology, University of Virginia, Charlottesville, VA 22904, United States.
Bioorg Med Chem. 2025 Feb 1;118:118045. doi: 10.1016/j.bmc.2024.118045. Epub 2024 Dec 18.
Chemical mitochondrial uncouplers are protonophoric, lipophilic small molecules that transport protons from the mitochondrial intermembrane space into the matrix independent of ATP synthase, thus uncoupling nutrient oxidation from ATP production. Our previous work identified BAM15 (IC 0.27 μM) as a potent and efficacious mitochondrial uncoupler with potential for obesity treatment. In this paper, we investigate in vitro and in vivo properties of hydroxylamine and hydrazine BAM15 derivatives and reveal the high uncoupling nature of these compounds. Our structure-activity relationship studies revealed that the hydroxylamine BAM15 analogs are more potent than hydrazine ones. For example, the most potent of the hydrazine series was 5a with an EC value of 4.6 μM and 103 % activity of BAM15 while compound 4e was the best among the hydroxylamine series with EC value of 340 nM and 118 % BAM15 mitochondrial uncoupling activity in rat L6 myoblasts. Pharmacokinetic profiling of 5a and 4e revealed low exposure (2-220 nM) and short half-life (15-27 min) in mice.
化学线粒体解偶联剂是一类质子载体型亲脂性小分子，它们可独立于ATP合酶将质子从线粒体膜间隙转运至基质中，从而使营养物质氧化与ATP生成解偶联。我们之前的研究确定BAM15（IC为0.27 μM）是一种高效且有效的线粒体解偶联剂，具有治疗肥胖症的潜力。在本文中，我们研究了羟胺和肼基BAM15衍生物的体外和体内特性，并揭示了这些化合物的高解偶联性质。我们的构效关系研究表明，羟胺类BAM15类似物比肼基类似物更有效。例如，肼基系列中最有效的是5a，其EC值为4.6 μM，活性为BAM15的103%，而化合物4e是羟胺系列中最好的，在大鼠L6成肌细胞中的EC值为340 nM，线粒体解偶联活性为BAM15的118%。对5a和4e的药代动力学分析显示，它们在小鼠体内的暴露量较低（2 - 220 nM），半衰期较短（15 - 27分钟）。
