(2R)-1-(4-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine | 946400-13-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (2R)-1-(4-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine
• 英文别名: (2R)-1-(4-Bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)-phenyl)-2-methylpiperazine；(2R)-1-(4-bromophenyl)sulfonyl-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine
• CAS: 946400-13-1
• 化学式: C₁₈H₁₇BrF₄N₂O₂S
• 分子量: 481.309
• InChiKey: RMSZYZLTJZMDKE-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  49
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  三氟丙酮酸甲酯 、 (2R)-1-(4-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine 在 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 2.25h， 生成
  参考文献：
  名称：

  Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

  摘要：

  11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11 beta-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11 beta-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.

  DOI：

  10.1021/ml300352x
• 作为产物：
  描述：

  (3R)-1-(4-氟-2-(三氟甲基)苯基)-3-甲基哌嗪 、 4-溴苯磺酰氯 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以88%的产率得到(2R)-1-(4-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine
  参考文献：
  名称：

  Efficacious 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors in the Diet-Induced Obesity Mouse Model

  摘要：

  Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11 beta-hydroxysteroid dehydrogenase type I (11 beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds I and 20 bound to human 11 beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11 beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

  DOI：

  10.1021/jm900639u

文献信息

• 11-Beta HSD 1 inhibitors
  申请人：Xiang Shaoyun Jason

  公开号：US20070219198A1

  公开（公告）日：2007-09-20

  This invention relates to inhibiting 11βHSD1.

  该发明涉及抑制11βHSD1。
• 11-Beta HSD1 Inhibitors
  申请人：Xiang Jason Shaoyun

  公开号：US20100029648A1

  公开（公告）日：2010-02-04

  This invention relates to inhibiting 11βHSD1.

  本发明涉及抑制11βHSD1。
• US7632838B2
  申请人：——

  公开号：US7632838B2

  公开（公告）日：2009-12-15
• Efficacious 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors in the Diet-Induced Obesity Mouse Model
  作者：Zhao-Kui Wan、Eva Chenail、Jason Xiang、Huan-Qiu Li、Manus Ipek、Joel Bard、Kristine Svenson、Tarek S. Mansour、Xin Xu、Xianbin Tian、Vipin Suri、Seung Hahm、Yuzhe Xing、Christian E. Johnson、Xiangping Li、Ariful Qadri、Darrell Panza、Mylene Perreault、James F. Tobin、Eddine Saiah

  DOI：10.1021/jm900639u

  日期：2009.9.10

  Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11 beta-hydroxysteroid dehydrogenase type I (11 beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds I and 20 bound to human 11 beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11 beta-HSD1 inhibition may be a valid target for the treatment of diabetes.
• Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes
  作者：Zhao-Kui Wan、Eva Chenail、Huan-Qiu Li、Manus Ipek、Jason Xiang、Vipin Suri、Seung Hahm、Joel Bard、Kristine Svenson、Xin Xu、Xianbin Tian、Mengmeng Wang、Xiangping Li、Christian E. Johnson、Ariful Qadri、Darrell Panza、Mylene Perreault、Tarek S. Mansour、James F. Tobin、Eddine Saiah

  DOI：10.1021/ml300352x

  日期：2013.1.10

  11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11 beta-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11 beta-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.