MDUK Oxford Neuromuscular Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, U.K.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
J Med Chem. 2020 Jul 23;63(14):7880-7891. doi: 10.1021/acs.jmedchem.0c00807. Epub 2020 Jul 10.
Utrophin modulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), which should be applicable to all patient populations. Following on from ezutromid, the first-generation utrophin modulator, we describe the development of a second generation of utrophin modulators, based on the bioisosteric replacement of the sulfone group with a phosphinate ester and substitution of the metabolically labile naphthalene with a haloaryl substituent. The improved physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, and , led to significantly better exposure compared to ezutromid and alleviation of the dystrophic phenotype in mice. While was found to have dose-limiting hepatotoxicity, and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next-generation utrophin modulators suitable for progression toward a future DMD therapy.
肌萎缩性侧索硬化症（DMD）的 utrophin 调节是一种很有前途的治疗策略，应该适用于所有患者群体。继第一代 utrophin 调节剂 ezutromid 之后，我们描述了第二代 utrophin 调节剂的开发，该调节剂基于生物等排体将砜基替换为膦酸酯，并将代谢不稳定的萘替换为卤代芳基取代基。改进的物理化学和吸收、分布、代谢和排泄（ADME）特性，进一步反映在最先进的化合物的增强的药代动力学特征中，与 ezutromid 相比，显著提高了 暴露量，并缓解了 小鼠的营养不良表型。虽然 被发现具有剂量限制的肝毒性，而 和其对映异构体表现出有限的脱靶效应，导致安全的特征，并突出其作为适合未来 DMD 治疗的下一代 utrophin 调节剂的潜在用途。
