Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, United States.
Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, United States.
Eur J Med Chem. 2024 Dec 15;280:116916. doi: 10.1016/j.ejmech.2024.116916. Epub 2024 Oct 5.
Small molecule mitochondrial uncouplers have gained traction for their potential therapeutic use against metabolic dysfunction-associated steatohepatitis (MASH). Herein, we report a novel imidazo[4,5-b]pyridine scaffold derived from iterative modifications of the potent uncoupler BAM15. Our structure-activity relationship (SAR) study demonstrated that this promising scaffold has a range of tolerated substitutions that allows for the modulation of uncoupling activity and in vivo pharmacokinetic properties. Specifically, compound SHS206 displayed an EC of 830 nM in L6 myoblasts and, importantly, showed no cytotoxicity in vitro or adverse effects in mice up to 1000 mg/kg. SHS206 was administered orally at 100 and 300 mg/kg in a GAN mouse model of MASH and was observed to lower liver triglyceride levels while food intake, body weight, temperature, organ weights, and cholesterol levels remained unaltered. Together, these findings illuminate imidazo[4,5-b]pyridine as a promising scaffold for the future development of mitochondrial uncouplers.
小分子线粒体解偶联剂因其在治疗代谢功能障碍相关脂肪性肝炎（MASH）方面的潜在应用而受到关注。在此，我们报告了一种新型咪唑并[4,5-b]吡啶骨架，它源自对强效解偶联剂 BAM15 的迭代修饰。我们的构效关系（SAR）研究表明，这个有前途的骨架具有一系列可耐受的取代基，允许调节解偶联活性和体内药代动力学特性。具体来说，化合物 SHS206 在 L6 成肌细胞中的 EC 为 830 nM，重要的是，在体外没有显示出细胞毒性，在高达 1000 mg/kg 的小鼠中也没有观察到不良反应。SHS206 在 MASH 的 GAN 小鼠模型中以 100 和 300 mg/kg 的剂量口服给药，观察到其降低肝脏甘油三酯水平，而食物摄入、体重、温度、器官重量和胆固醇水平保持不变。总之，这些发现阐明了咪唑并[4,5-b]吡啶作为未来线粒体解偶联剂开发的有前途的骨架。
