期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 14, 页码 7880-7891出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00807
关键词
-
资金
- Summit Therapeutics plc
- Medical Research Council [1501AV003/CA2]
- MRC [MC_U137761449, MR/N010698/1, G0801763, G0700377, MC_UU_12021/2, G0300284, MC_U137761451] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据