(2-{3-[(3-Benzoylamino-propyl)-methyl-carbamoyl]-naphthalen-2-yl}-1-naphthalen-1-yl-2-oxo-ethyl)-phosphonic acid diethyl ester | 429677-04-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (2-{3-[(3-Benzoylamino-propyl)-methyl-carbamoyl]-naphthalen-2-yl}-1-naphthalen-1-yl-2-oxo-ethyl)-phosphonic acid diethyl ester
• CAS: 429677-04-3
• 化学式: C₃₈H₃₉N₂O₆P
• 分子量: 650.711
• InChiKey: LFXHUNBIEDYIHT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.08
• 重原子数：
  47.0
• 可旋转键数：
  14.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  102.01
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (2-{3-[(3-Benzoylamino-propyl)-methyl-carbamoyl]-naphthalen-2-yl}-1-naphthalen-1-yl-2-oxo-ethyl)-phosphonic acid diethyl ester 在 吡啶 、 三甲基溴硅烷 、 盐酸 作用下， 反应 1.5h， 以51%的产率得到(2-{3-[(3-Benzoylamino-propyl)-methyl-carbamoyl]-naphthalen-2-yl}-1-naphthalen-1-yl-2-oxo-ethyl)-phosphonic acid
  参考文献：
  名称：

  Nonpeptide Inhibitors of Cathepsin G:  Optimization of a Novel β-Ketophosphonic Acid Lead by Structure-Based Drug Design

  摘要：

  The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.

  DOI：

  10.1021/ja017506h
• 作为产物：
  描述：

  1-萘基甲基膦酸二乙酯 在 正丁基锂 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 29.5h， 生成 (2-{3-[(3-Benzoylamino-propyl)-methyl-carbamoyl]-naphthalen-2-yl}-1-naphthalen-1-yl-2-oxo-ethyl)-phosphonic acid diethyl ester
  参考文献：
  名称：

  Nonpeptide Inhibitors of Cathepsin G:  Optimization of a Novel β-Ketophosphonic Acid Lead by Structure-Based Drug Design

  摘要：

  The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.

  DOI：

  10.1021/ja017506h