4-((3R)-3-methyl-4-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile | 1415042-10-2

• 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: 4-((3R)-3-methyl-4-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
• CAS: 1415042-10-2
• 化学式: C₂₀H₁₉F₆N₃O₃S₂
• 分子量: 527.512
• InChiKey: UESNOCDFBIVQRW-GKOGFXNCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.31
• 重原子数：
  34.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  84.64
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  4-((3R)-3-methyl-4-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile 在 potassium hydroxide 作用下， 以 叔丁醇 为溶剂， 反应 0.33h， 生成 4-((R)-3-methyl-4-((5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzamide 、 4-((R)-3-methyl-4-((5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzamide
  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：

  1,1,1-三氟丙酮 、 (R)-4-(3-methyl-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 0.25h， 以69%的产率得到4-((3R)-3-methyl-4-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
  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