2-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)isothiazolidine 1,1-dioxide | 1247702-75-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)isothiazolidine 1,1-dioxide
• 英文别名: 5-(1,1-dioxo-isothiazolidin-2-yl)-2-(naphthalene-2-yl)benzo[d]oxazole；2-(2-Naphthalen-2-yl-1,3-benzoxazol-5-yl)-1,2-thiazolidine 1,1-dioxide
• CAS: 1247702-75-5
• 化学式: C₂₀H₁₆N₂O₃S
• 分子量: 364.425
• InChiKey: CLJWGCRZFCQTOP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  71.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,4-diaminophenol dihydrochloride 在 sodium hydride 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 2-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)isothiazolidine 1,1-dioxide
  参考文献：
  名称：

  2-Arylbenzo[d]oxazole Phosphinate Esters as Second-Generation Modulators of Utrophin for the Treatment of Duchenne Muscular Dystrophy

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.0c00807

文献信息

• [EN] BENZOXAZOLES FOR THE TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY<br/>[FR] BENZOXAZOLES POUR LE TRAITEMENT DE LA DYSTROPHIE MUSCULAIRE DE DUCHENNE
  申请人：BIOMARIN IGA LTD

  公开号：WO2010112093A1

  公开（公告）日：2010-10-07

  Compounds of formula (I), wherein R1, R2, R3, X and n are as defined herein, are useful for the treatment or prophylaxis of conditions such as Duchenne muscular dystrophy, Becker muscular dystrophy, and cachexia.

  化合物公式（I），其中R1，R2，R3，X和n的定义如本文所述，可用于治疗或预防如杜氏肌萎缩症，贝克肌萎缩症和消瘦等疾病。
• 2-Arylbenzo[<i>d</i>]oxazole Phosphinate Esters as Second-Generation Modulators of Utrophin for the Treatment of Duchenne Muscular Dystrophy
  作者：Arran Babbs、Adam Berg、Maria Chatzopoulou、Kay E. Davies、Stephen G. Davies、Benjamin Edwards、David J. Elsey、Enrico Emer、Simon Guiraud、Shawn Harriman、Cristina Lecci、Lee Moir、David Peters、Neil Robinson、Jessica A. Rowley、Angela J. Russell、Sarah E. Squire、Jonathon M. Tinsley、Francis X. Wilson、Graham M. Wynne

  DOI：10.1021/acs.jmedchem.0c00807

  日期：2020.7.23

  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.