N-((1R,2S)-1-(3-chloro-4-cyanophenoxy)-1-(6-methoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-((1R,2S)-1-(3-chloro-4-cyanophenoxy)-1-(6-methoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide
• 英文别名: N-[(1R,2S)-1-(3-chloro-4-cyanophenoxy)-1-(6-methoxypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide
• 化学式: C₁₉H₁₈ClF₂N₃O₃
• 分子量: 409.82
• InChiKey: ADTCHDOIIJGUKX-GTNSWQLSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  84.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,2-二氟丙酸 、 4-((1R,2S)-2-amino-1-(6-methoxypyridin-3-yl)propoxy)-2-chlorobenzonitrile 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以87%的产率得到N-((1R,2S)-1-(3-chloro-4-cyanophenoxy)-1-(6-methoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide
  参考文献：
  名称：

  Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile

  摘要：

  Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.

  DOI：

  10.1021/acs.jmedchem.7b01690

文献信息

• Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile
  作者：Lena Ripa、Karl Edman、Matthew Dearman、Goran Edenro、Ramon Hendrickx、Victoria Ullah、Hui-Fang Chang、Matti Lepistö、Dave Chapman、Stefan Geschwindner、Lisa Wissler、Petter Svanberg、Karolina Lawitz、Jesper Malmberg、Antonios Nikitidis、Roine I. Olsson、James Bird、Antoni Llinas、Tove Hegelund-Myrbäck、Markus Berger、Philip Thorne、Richard Harrison、Christian Köhler、Tomas Drmota

  DOI：10.1021/acs.jmedchem.7b01690

  日期：2018.3.8

  Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.