(5-bromothiophen-2-yl)(2-fluoro-3-methoxyphenyl)methanone

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (5-bromothiophen-2-yl)(2-fluoro-3-methoxyphenyl)methanone
• 英文别名: (5-Bromothiophen-2-yl)-(2-fluoro-3-methoxyphenyl)methanone；(5-bromothiophen-2-yl)-(2-fluoro-3-methoxyphenyl)methanone
• 化学式: C₁₂H₈BrFO₂S
• 分子量: 315.163
• InChiKey: RTUVXDWBZYASOI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  54.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (5-bromothiophen-2-yl)(2-fluoro-3-methoxyphenyl)methanone 在 吡啶 、 四(三苯基膦)钯 、 caesium carbonate 作用下， 以 甲醚 、 水 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Targeted Endocrine Therapy: Design, Synthesis, and Proof-of-Principle of 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors in Bone Fracture Healing

  摘要：

  Current therapies of steroid hormone-dependent diseases predominantly alter steroid hormone concentrations (or their actions) in plasma, in target and nontarget tissues alike, rather than in target organs only. Targeted therapy through the inhibition of steroidogenic enzymes may pose an attractive alternative with much less side effects. Here, we describe the design of a nanomolar potent 17 beta-hydroxysteroid dehydrogenase type 2 (17 beta-HSD2) inhibitor (compound 15) and successful targeted intracrine therapy in a mouse bone fracture model. Blockade of 17 beta-HSD2 in bone is thought to increase intracellular estradiol (E2) and testosterone (T), which thereby inhibits bone resorption by osteoclasts and stimulates bone formation by osteoblasts, respectively. Administration of compound 15 in the mouse fracture model strongly increases the mechanical stability of the healing fractured bone because of a larger periosteal callus with newly formed bone without changing the plasma E2 and T concentrations. Steroidogenic 17 beta-HSD2 inhibition thus enables targeted intracrine therapy.

  DOI：

  10.1021/acs.jmedchem.8b01493
• 作为产物：
  描述：

  2-溴噻吩 、 2-氟-3-甲氧基苯甲酰氯 在 aluminum (III) chloride 作用下， 以 二氯甲烷 为溶剂， 以57%的产率得到(5-bromothiophen-2-yl)(2-fluoro-3-methoxyphenyl)methanone
  参考文献：
  名称：

  雌激素依赖性疾病的治疗：设计，合成和分析具有亚纳摩尔级IC50的选择性17β-HSD1抑制剂，以进行原理验证研究。

  摘要：

  当前用于雌激素依赖性疾病子宫内膜异位症的内分泌治疗剂通常会引起相当大的副作用，因为它们通过全身性地降低雌激素作用而起作用。最近的方法利用了以下事实：血浆中富含的雌激素雌激素（E1）在靶细胞中被17β-羟类固醇脱氢酶1型（17β-HSD1）激活为高雌激素雌二醇（E2）。 。17β-HSD1在子宫内膜异位症中过表达，因此是治疗该疾病的有希望的靶标，并有望减少与靶标相关的副作用。我们最近描述的具有磺酰胺部分的双环取代的羟基苯基亚甲酮类的强抑制剂在17β-HSD1的生理对手——17βHSD2上具有高分子量和低选择性。我们描述了导致（5-（3,5-二氯-4-甲氧基苯基）噻吩-2-基）（2,6-二氟-3-羟苯基）甲酮20的发现的结构优化，它显示了亚纳摩尔级对17β-HSD1的IC50以及对2型酶，雌激素受体α和β以及一系列肝CYP酶的高选择性。该化合物在AMES II分析中既未显示出细胞毒性，也未显示

  DOI：

  10.1016/j.ejmech.2016.11.004

文献信息

• Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC 50 for a proof-of-principle study
  作者：Ahmed S. Abdelsamie、Chris J. van Koppen、Emmanuel Bey、Mohamed Salah、Carsten Börger、Lorenz Siebenbürger、Matthias W. Laschke、Michael D. Menger、Martin Frotscher

  DOI：10.1016/j.ejmech.2016.11.004

  日期：2017.2

  discovery of (5-(3,5-dichloro-4-methoxyphenyl)thiophen-2-yl)(2,6-difluoro-3-hydroxyphenyl)methanone 20, which displayed a sub-nanomolar IC50 towards 17β-HSD1 as well as high selectivity over the type 2 enzyme, the estrogen receptors α and β and a range of hepatic CYP enzymes. The compound did neither show cellular toxicity, nor PXR activation nor mutagenicity in the AMES II assay. Additional favourable pharmacokinetic

  当前用于雌激素依赖性疾病子宫内膜异位症的内分泌治疗剂通常会引起相当大的副作用，因为它们通过全身性地降低雌激素作用而起作用。最近的方法利用了以下事实：血浆中富含的雌激素雌激素（E1）在靶细胞中被17β-羟类固醇脱氢酶1型（17β-HSD1）激活为高雌激素雌二醇（E2）。 。17β-HSD1在子宫内膜异位症中过表达，因此是治疗该疾病的有希望的靶标，并有望减少与靶标相关的副作用。我们最近描述的具有磺酰胺部分的双环取代的羟基苯基亚甲酮类的强抑制剂在17β-HSD1的生理对手——17βHSD2上具有高分子量和低选择性。我们描述了导致（5-（3,5-二氯-4-甲氧基苯基）噻吩-2-基）（2,6-二氟-3-羟苯基）甲酮20的发现的结构优化，它显示了亚纳摩尔级对17β-HSD1的IC50以及对2型酶，雌激素受体α和β以及一系列肝CYP酶的高选择性。该化合物在AMES II分析中既未显示出细胞毒性，也未显示
• Targeted Endocrine Therapy: Design, Synthesis, and <i>Proof-of-Principle</i> of 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors in Bone Fracture Healing
  作者：Ahmed S. Abdelsamie、Steven Herath、Yannik Biskupek、Carsten Börger、Lorenz Siebenbürger、Mohamed Salah、Claudia Scheuer、Sandrine Marchais-Oberwinkler、Martin Frotscher、Tim Pohlemann、Michael D. Menger、Rolf W. Hartmann、Matthias W. Laschke、Chris J. van Koppen

  DOI：10.1021/acs.jmedchem.8b01493

  日期：2019.2.14

  Current therapies of steroid hormone-dependent diseases predominantly alter steroid hormone concentrations (or their actions) in plasma, in target and nontarget tissues alike, rather than in target organs only. Targeted therapy through the inhibition of steroidogenic enzymes may pose an attractive alternative with much less side effects. Here, we describe the design of a nanomolar potent 17 beta-hydroxysteroid dehydrogenase type 2 (17 beta-HSD2) inhibitor (compound 15) and successful targeted intracrine therapy in a mouse bone fracture model. Blockade of 17 beta-HSD2 in bone is thought to increase intracellular estradiol (E2) and testosterone (T), which thereby inhibits bone resorption by osteoclasts and stimulates bone formation by osteoblasts, respectively. Administration of compound 15 in the mouse fracture model strongly increases the mechanical stability of the healing fractured bone because of a larger periosteal callus with newly formed bone without changing the plasma E2 and T concentrations. Steroidogenic 17 beta-HSD2 inhibition thus enables targeted intracrine therapy.