Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford OX1 3PT, UK.
Bioorg Med Chem. 2022 Sep 1;69:116812. doi: 10.1016/j.bmc.2022.116812. Epub 2022 May 18.
A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.
一种有潜力治疗所有杜氏肌营养不良症（DMD）患者群体的治疗方法是肌联蛋白调节。Ezutromid 是第一代肌联蛋白调节剂，后来发现它通过拮抗芳香烃受体起作用，进入了 2 期临床试验。尽管中期数据显示了靶标结合和功能改善，但 Ezutromid 最终未能达到其临床终点。我们最近描述了一种新型酰腙肌联蛋白调节剂的鉴定，它与 Ezutromid 的作用机制不同。在这项研究中，我们报告了我们对此酰腙系列的早期优化研究。新型类似物在基于细胞的测定中具有显著提高的效力，增加了 sp 特征并降低了亲脂性，这也改善了它们的物理化学性质。一个具有这些属性的代表性新类似物增加了营养不良小鼠细胞中的肌联蛋白蛋白，表明它可以用作化学工具，揭示肌联蛋白上调作为 DMD 治疗干预策略的新见解。
