tert-butyl (3R)-3-(3-{6-[bis(methylsulfonyl)amino]-3-pyridinyl}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate | 468069-18-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子
• 英文名称: tert-butyl (3R)-3-(3-{6-[bis(methylsulfonyl)amino]-3-pyridinyl}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate
• 英文别名: tert-butyl (3R)-3-[3-[6-[bis(methylsulfonyl)amino]pyridin-3-yl]-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate
• CAS: 468069-18-3
• 化学式: C₂₅H₃₈N₄O₇S₂
• 分子量: 570.731
• InChiKey: CCCJLEQZXORREK-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  38
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  166
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  tert-butyl (3R)-3-(3-{6-[bis(methylsulfonyl)amino]-3-pyridinyl}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate 在 sodium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以0.08 g的产率得到(3R)-6-cyclohexyl-3-(3-{6-[(methylsulfonyl)amino]-3-pyridinyl}-1,2,4-oxadiazol-5-yl)hexanoic acid
  参考文献：
  名称：

  Potent and Selective Nonpeptidic Inhibitors of Procollagen C-Proteinase

  摘要：

  6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (K-i 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (> 10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 mu M and was very effective at penetrating human skin in vitro with a TED flux of 1.5 mu g/cm(2)/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.

  DOI：

  10.1021/jm061010z
• 作为产物：
  描述：

  在 氨 、 三乙胺 作用下， 以 乙醇 、 三氯乙烷 为溶剂， 生成 tert-butyl (3R)-3-(3-{6-[bis(methylsulfonyl)amino]-3-pyridinyl}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate
  参考文献：
  名称：

  Potent and Selective Nonpeptidic Inhibitors of Procollagen C-Proteinase

  摘要：

  6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (K-i 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (> 10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 mu M and was very effective at penetrating human skin in vitro with a TED flux of 1.5 mu g/cm(2)/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.

  DOI：

  10.1021/jm061010z