Inhibitor 61

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Inhibitor 61
• 英文别名: 5-[[5-[[(2S)-3-carboxy-1-(7-methoxy-1,3-benzoxazol-2-yl)-1-oxopropan-2-yl]carbamoyl]pyridin-2-yl]methylsulfamoyl]-2-hydroxybenzoic acid
• 化学式: C₂₆H₂₂N₄O₁₁S
• 分子量: 598.547
• InChiKey: SIRDBTDSADKLJV-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  244
• 氢给体数：
  5
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  6-(溴甲基)烟酸甲酯 在 palladium on activated charcoal N-甲基吗啉 、 lithium hydroxide 、 sodium azide 、 氢气 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 20.0~90.0 ℃ 、137.9 kPa 条件下， 反应 0.83h， 生成 Inhibitor 61
  参考文献：
  名称：

  Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design

  摘要：

  The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S-4 pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K-i = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K-i values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K-i = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.

  DOI：

  10.1021/jm020230j

文献信息

• Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design
  作者：Ingrid C. Choong、Willard Lew、Dennis Lee、Phuongly Pham、Matthew T. Burdett、Joni W. Lam、Christian Wiesmann、Tinh N. Luong、Bruce Fahr、Warren L. DeLano、Robert S. McDowell、Darin A. Allen、Daniel A. Erlanson、Eric M. Gordon、Tom O'Brien

  DOI：10.1021/jm020230j

  日期：2002.11.1

  The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S-4 pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K-i = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K-i values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K-i = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.