(5-(3-amino-4-hydroxyphenyl)thiophen-2-yl)(2,4,5-trifluoro-3-hydroxyphenyl)methanone

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (5-(3-amino-4-hydroxyphenyl)thiophen-2-yl)(2,4,5-trifluoro-3-hydroxyphenyl)methanone
• 英文别名: [5-(3-Amino-4-hydroxyphenyl)thiophen-2-yl]-(2,4,5-trifluoro-3-hydroxyphenyl)methanone；[5-(3-amino-4-hydroxyphenyl)thiophen-2-yl]-(2,4,5-trifluoro-3-hydroxyphenyl)methanone
• 化学式: C₁₇H₁₀F₃NO₃S
• 分子量: 365.333
• InChiKey: IZLPCNQZQKWOPJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  112
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-氯 3-碘-苯甲酸甲酯 在 四(三苯基膦)钯 、 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 potassium acetate 、 caesium carbonate 作用下， 以 乙二醇二甲醚 、 水 、 二甲基亚砜 、 甲苯 为溶剂， 反应 38.0h， 生成 (5-(3-amino-4-hydroxyphenyl)thiophen-2-yl)(2,4,5-trifluoro-3-hydroxyphenyl)methanone
  参考文献：
  名称：

  Highly Potent 17β-HSD2 Inhibitors with a Promising Pharmacokinetic Profile for Targeted Osteoporosis Therapy

  摘要：

  Intracellular elevation of E2 levels in bone by inhibition of 17 beta hydroxysteroid dehydrogenase type 2 (17 beta-HSD2) without affecting systemic E2 levels is an attractive approach for a targeted therapy against osteoporosis, a disease which is characterized by loss of bone mineral density. Previously identified inhibitor A shows high potency on human and mouse 17 beta-HSD2, but poor pharmacokinetic properties when applied perorally in mice. A combinatorial chemistry approach was utilized to synthesize truncated derivatives of A, leading to highly potent compounds with activities in the low nanomolar to picomolar range. Compound 33, comparable to A in terms of inhibitor potency against both human and mouse enzymes, displays high in vitro metabolic stability in human and mouse liver S9 fraction as well as low toxicity and moderate hepatic CYP inhibition. Thus, compound 33 showed a highly improved peroral pharmacokinetic profile in comparison to A, making 33 a promising candidate for further development.

  DOI：

  10.1021/acs.jmedchem.8b01373

文献信息

• Inhibitors of 17Beta-Hydroxysteroid Dehydrogenases Type 1 and Type 2
  申请人：ELEXOPHARM GMBH

  公开号：US20160318895A1

  公开（公告）日：2016-11-03

  Provided herein are non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 and type 2 (17β-HSD1 and 17β-HSD2) inhibitors, their production and use, especially for the treatment and for prophylaxis of hormone-related diseases.

  提供的是非甾体的17β-羟基类固醇脱氢酶1型和2型（17β-HSD1和17β-HSD2）抑制剂，它们的生产和应用，尤其是用于治疗和预防激素相关疾病。
• INHIBITORS OF 17BETA-HYDROXYSTEROID DEHYDROGENASES TYPE 1 AND TYPE 2
  申请人：Elexopharm GmbH

  公开号：EP3089969A2

  公开（公告）日：2016-11-09
• US9884839B2
  申请人：——

  公开号：US9884839B2

  公开（公告）日：2018-02-06
• Highly Potent 17β-HSD2 Inhibitors with a Promising Pharmacokinetic Profile for Targeted Osteoporosis Therapy
  作者：Lorenz Siebenbuerger、Victor Hernandez-Olmos、Ahmed S. Abdelsamie、Martin Frotscher、Chris J. van Koppen、Sandrine Marchais-Oberwinkler、Claudia Scheuer、Matthias W. Laschke、Michael D. Menger、Carsten Boerger、Rolf W. Hartmann

  DOI：10.1021/acs.jmedchem.8b01373

  日期：2018.12.13

  Intracellular elevation of E2 levels in bone by inhibition of 17 beta hydroxysteroid dehydrogenase type 2 (17 beta-HSD2) without affecting systemic E2 levels is an attractive approach for a targeted therapy against osteoporosis, a disease which is characterized by loss of bone mineral density. Previously identified inhibitor A shows high potency on human and mouse 17 beta-HSD2, but poor pharmacokinetic properties when applied perorally in mice. A combinatorial chemistry approach was utilized to synthesize truncated derivatives of A, leading to highly potent compounds with activities in the low nanomolar to picomolar range. Compound 33, comparable to A in terms of inhibitor potency against both human and mouse enzymes, displays high in vitro metabolic stability in human and mouse liver S9 fraction as well as low toxicity and moderate hepatic CYP inhibition. Thus, compound 33 showed a highly improved peroral pharmacokinetic profile in comparison to A, making 33 a promising candidate for further development.