(3R)-6-cyclohexyl-N-hydroxy-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]hexanamide

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (3R)-6-cyclohexyl-N-hydroxy-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]hexanamide
• 英文别名: (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexyl-N-hydroxyhexanamide
• 化学式: C₁₅H₂₆N₄O₃
• 分子量: 310.396
• InChiKey: ARIPGELMXPEYAH-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl)-1,2,4-oxadiazole-3-carboxylate 在 sodium tetrahydroborate 、 氨 、 三乙胺 、 三氟乙酸 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 40.5h， 生成 (3R)-6-cyclohexyl-N-hydroxy-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]hexanamide
  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

文献信息

• US7214694B2
  申请人：——

  公开号：US7214694B2

  公开（公告）日：2007-05-08
• Potent and Selective Nonpeptidic Inhibitors of Procollagen C-Proteinase
  作者：Paul V. Fish、Gillian A. Allan、Simon Bailey、Julian Blagg、Richard Butt、Michael G. Collis、Doris Greiling、Kim James、Jackie Kendall、Andrew McElroy、Dawn McCleverty、Charlotte Reed、Robert Webster、Gavin A. Whitlock

  DOI：10.1021/jm061010z

  日期：2007.7.1

  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.