2-(5-{(1R)-4-CYCLOHEXYL-1-[2-(HYDROXYAMINO)-2-OXOETHYL]BUTYL}-1,2,4-OXADIAZOL-3-YL)ISONICOTINIC ACID

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 2-(5-{(1R)-4-CYCLOHEXYL-1-[2-(HYDROXYAMINO)-2-OXOETHYL]BUTYL}-1,2,4-OXADIAZOL-3-YL)ISONICOTINIC ACID
• 英文别名: 2-[5-[(3R)-6-cyclohexyl-1-(hydroxyamino)-1-oxohexan-3-yl]-1,2,4-oxadiazol-3-yl]pyridine-4-carboxylic acid
• 化学式: C₂₀H₂₆N₄O₅
• 分子量: 402.45
• InChiKey: BCLDMTLBRZOHBQ-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  138
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid 在 lithium hydroxide 、 三乙胺 、 N,N'-羰基二咪唑 、 三氟乙酸 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 xylene 为溶剂， 反应 6.5h， 生成 2-(5-{(1R)-4-CYCLOHEXYL-1-[2-(HYDROXYAMINO)-2-OXOETHYL]BUTYL}-1,2,4-OXADIAZOL-3-YL)ISONICOTINIC 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

文献信息

• 3-heterocyclylpropanohydroxamic acid PCP inhibitors
  申请人：——

  公开号：US20030069291A1

  公开（公告）日：2003-04-10

  Compounds of formula (I): 1 and their salts, solvates, hydrates and prodrugs are useful PCP inhibitors, processes for making the same, compositions comprising the same, and methods of treating a PCP-mediated condition or disease using the same.

  式(I)的化合物及其盐、溶剂合物、水合物和前药是有用的PCP抑制剂，制备这些化合物的方法，包含这些化合物的组合物，以及使用这些化合物治疗PCP介导的疾病或病症的方法。
• 3-HETEROCYCLYLPROPANOHYDROXAMIC ACID AS PROCOLLAGEN C-PROTEINASE INHIBITORS
  申请人：Pfizer Limited

  公开号：EP1373264B1

  公开（公告）日：2004-12-22
• US6821972B2
  申请人：——

  公开号：US6821972B2

  公开（公告）日：2004-11-23
• 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.