(R)-4-(3-methyl-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile | 1257229-86-9

• 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: (R)-4-(3-methyl-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
• 英文别名: 4-[(3R)-3-methyl-4-thiophen-2-ylsulfonylpiperazin-1-yl]-3-(trifluoromethyl)benzonitrile
• CAS: 1257229-86-9
• 化学式: C₁₇H₁₆F₃N₃O₂S₂
• 分子量: 415.46
• InChiKey: IPPXZMYPOICKKP-GFCCVEGCSA-N

物化性质

• 沸点：
  555.2±60.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  三氟丙酮酸甲酯 、 (R)-4-(3-methyl-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile 在 lithium diisopropyl amide 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 0.83h， 以78%的产率得到methyl 2-[5-({(2R)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxypropanoate
  参考文献：
  名称：

  [EN] 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11-BETA HSD1) INHIBITORS
  [FR] INHIBITEURS DE 11-BÊTA HSD1

  摘要：

  公开号：

  WO2010141550A3
• 作为产物：
  描述：

  2-噻吩磺酰氯 、 4-[(3R)-3-甲基哌嗪-1-基]-3-(三氟甲基)苯甲腈 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以96%的产率得到(R)-4-(3-methyl-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
  参考文献：
  名称：

  [EN] 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11-BETA HSD1) INHIBITORS
  [FR] INHIBITEURS DE 11-BÊTA HSD1

  摘要：

  公开号：

  WO2010141550A3

文献信息

• 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.