(1R,2S)-2-amino-1-(3-chlorophenyl)-3-methylbutan-1-ol

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (1R,2S)-2-amino-1-(3-chlorophenyl)-3-methylbutan-1-ol
• 化学式: C₁₁H₁₆ClNO
• 分子量: 213.707
• InChiKey: VQQGMLLHUVGTPB-WDEREUQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  46.2
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1R,2S)-2-amino-1-(3-chlorophenyl)-3-methylbutan-1-ol 在 copper(l) iodide 、 N,N-二甲基甘氨酸 、 caesium carbonate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 生成 N-[(1R,2S)-1-(3-chlorophenyl)-3-methyl-1-{[1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl]oxy}butan-2-yl]-2,2,2-trifluoroacetamide
  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
• 作为产物：
  描述：

  (3-chlorophenyl)magnesium bromide 在 盐酸 、 aluminum isopropoxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 异丙醇 、 甲苯 为溶剂， 反应 21.0h， 生成 (1R,2S)-2-amino-1-(3-chlorophenyl)-3-methylbutan-1-ol
  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.