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, 30 and 27, led to significantly better in vivo exposure compared to ezutromid and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 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.

中文翻译：

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2-芳基苯并[d]恶唑膦酸酯作为促卵磷脂的第二代调节剂，用于治疗杜兴肌营养不良。

促性腺激素调节是一种针对杜兴氏肌营养不良症（DMD）的有前途的治疗策略，应适用于所有患者人群。继第一代促性腺激素调节剂ezutromid之后，我们描述了第二代促性卵磷脂调节剂的开发，其基础是用次膦酸酯对砜基团进行生物等位取代，并用卤代芳基取代基取代代谢不稳定的萘。物理化学和吸收，分布，代谢和排泄（ADME）特性的改善，进一步体现在最先进的化合物30和27的增强的药代动力学特征上，导致体内的明显改善暴露与Ezutromid相比和mdx小鼠营养不良表型的缓解。虽然发现30种具有剂量限制性肝毒性，但27种及其对映异构体显示出有限的脱靶效应，因此具有安全性，并突出了其潜在的实用性，可作为适于未来DMD治疗发展的下一代促卵磷脂调节剂。