Chatzopoulou Maria, Emer Enrico, Lecci Cristina, Rowley Jessica A, Casagrande Anne-Sophie, Moir Lee, Squire Sarah E, Davies Stephen G, Harriman Shawn, Wynne Graham M, Wilson Francis X, Davies Kay E, Russell Angela J
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K.
Evoetec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Milton, Abingdon OX14 4RZ, U.K.
ACS Med Chem Lett. 2020 Nov 4;11(12):2421-2427. doi: 10.1021/acsmedchemlett.0c00405. eCollection 2020 Dec 10.
Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. In this work we describe how less lipophilic analogues retained utrophin modulatory activity in a reporter gene assay, upregulated utrophin protein in dystrophic mouse muscle cells, but also had improved physicochemical and ADME properties. Notably, ClogP was found to directly correlate with pIC in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound showed a balanced profile (H2K EC: 4.17 μM, solubility: 477 μM, mouse hepatocyte > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay.
肌动蛋白调节是杜氏肌营养不良症的一种疾病修饰治疗策略，适用于所有患者群体。为了改善同类首个临床候选药物依佐米德的不理想特性，研发了第二代带有次膦酸酯部分的肌动蛋白调节剂。这种修饰显著改善了物理化学性质和药物代谢动力学性质，但发现主要先导分子之一具有剂量限制性肝毒性。在这项工作中，我们描述了亲脂性较低的类似物如何在报告基因测定中保留肌动蛋白调节活性，在营养不良小鼠肌肉细胞中上调肌动蛋白蛋白，同时还改善了物理化学性质和药物代谢动力学性质。值得注意的是，发现辛醇/水分配系数（ClogP）与HepG2细胞中的pIC直接相关，因此该系列药物具有潜在更安全的毒理学特性。化合物显示出平衡的特性（H2K EC：4.17 μM，溶解度：477 μM，小鼠肝细胞半衰期> 240分钟），并且在蛋白质印迹测定中使肌动蛋白蛋白增加了1.6倍。
