methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoate | 212610-34-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoate
• 英文别名: methyl (2R)-2-[(1R)-1-hydroxyethyl]-4-methylpentanoate
• CAS: 212610-34-9
• 化学式: C₉H₁₈O₃
• 分子量: 174.24
• InChiKey: JZGRPEBQQLCJEG-HTQZYQBOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  12
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoate 在 N-甲基吗啉 、 吡啶 、 lithium hydroxide 、 sodium hydroxide 、 氰基磷酸二乙酯 、 potassium carbonate 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 62.0h， 生成 (R)-2-{(S)-1-[Formyl-(tetrahydro-pyran-2-yloxy)-amino]-ethyl}-4-methyl-pentanoic acid [(1R,2S)-4-({amino-[(E)-methanesulfonylimino]-methyl}-amino)-2-methyl-1-(thiazol-2-ylcarbamoyl)-butyl]-amide
  参考文献：
  名称：

  Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)

  摘要：

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.

  DOI：

  10.1021/jm0102654
• 作为产物：
  描述：

  methyl (2R,3R)-2-(2-methyl-2-propen-1-yl)-3-hydroxybutanoate 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 以96%的产率得到methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoate
  参考文献：
  名称：

  Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)

  摘要：

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.

  DOI：

  10.1021/jm0102654

文献信息

• Formamide compounds as therapeutic agents
  申请人：Glaxo Wellcome Inc.

  公开号：US06191150B1

  公开（公告）日：2001-02-20

  A family of compounds having the general structural formula where W is a reverse hydroxamic acid group, and R1, R2, R3, R4, R5 and R6 are as described in the specification, or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

  具有一般结构式的化合物家族，其中W是一个反向羟肟酸基团，而R1、R2、R3、R4、R5和R6如规范中所述，或其药学上可接受的盐、溶剂化合物、生物水解酯、生物水解酰胺、亲和试剂或其前药。
• N-Hydroxyformamide peptidomimetics as TACE/Matrix metalloprotease inhibitors: oral activity via P1′ isobutyl substitution
  作者：David L. Musso、Marc W. Andersen、Robert C. Andrews、Richard Austin、Elizabeth J. Beaudet、J.David Becherer、Dulce G. Bubacz、D.Mark Bickett、Joseph H. Chan、James G. Conway、David J. Cowan、Michael D. Gaul、Kimberly C. Glennon、Kevin M. Hedeen、Millard H. Lambert、M.Anthony Leesnitzer、Darryl L. McDougald、Justin L. Mitchell、Marcia L. Moss、Michael H. Rabinowitz、Michele C. Rizzolio、Lee T. Schaller、Jennifer B. Stanford、Timothy K. Tippin、Janet R. Warner、L.Graham Whitesell、Robert W. Wiethe

  DOI：10.1016/s0960-894x(01)00377-8

  日期：2001.8

  N-Hydroxyformamide-class metalloprotease inhibitors were designed and synthesized, which have potent broad-spectrum activity versus matrix metalloproteases and TNF-x converting enzyme (TACE). Compound 13c possesses good oral and intravenous pharmacokinetics in the rat and dog. (C) 2001 Elsevier Science Ltd. All rights reserved.