(3R,4S)-2,2-difluoro-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid | 745773-39-1

• 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: (3R,4S)-2,2-difluoro-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid
• CAS: 745773-39-1
• 化学式: C₁₆H₂₁F₂NO₅
• 分子量: 345.343
• InChiKey: SIWUYSHFGUUHMS-NWDGAFQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  95.9
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R,4S)-2,2-difluoro-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid 在 盐酸 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成
  参考文献：
  名称：

  Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors

  摘要：

  A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, Which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

  DOI：

  10.1021/jm00079a001
• 作为产物：
  描述：

  BOC-PHE-甲氧基甲胺 在 lithium hydroxide 、 lithium aluminium tetrahydride 、 锌 作用下， 以 四氢呋喃 、 乙醚 、 乙腈 为溶剂， 反应 2.83h， 生成 (3R,4S)-2,2-difluoro-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid
  参考文献：
  名称：

  二氟酮类肽模拟物提示阿尔茨海默氏病的γ-分泌酶有较大的S1口袋：这对抑制剂设计具有重要意义。

  摘要：

  与阿尔茨海默氏病的病因有关的淀粉样β蛋白（Abeta）的生成的最后一步是通过γ-分泌酶在淀粉样前体蛋白（APP）的跨膜区域内进行蛋白水解。尽管γ-分泌酶被认为是治疗设计的重要目标，但尚未被充分表征或确定。我们实验室中先前使用基于底物的二氟酮和二氟醇过渡态类似物抑制剂的研究表明，γ-分泌酶是天冬氨酰蛋白酶，具有宽松的序列特异性。为了进一步表征γ-分泌酶的活性位点，我们制备了一系列在P1位置具有不同空间体积的二氟酮肽类似物，并测试了这些化合物抑制APP转染细胞中Abeta产生的能力。庞大的脂肪族P1侧链（如仲丁基或环己基甲基）的引入导致增加的γ-分泌酶抑制能力，这表明一个大的S1口袋可容纳这些取代基，并为松散的序列特异性提供了进一步的证据。环己基甲基P1取代基可将N端截短为低分子量化合物（<600 Da），该化合物有效地阻断了Abeta的产生（IC（50）约为5 microM）。该发现表明，最

  DOI：

  10.1021/jm000100f

文献信息

• Difluoro Ketone Peptidomimetics Suggest a Large S1 Pocket for Alzheimer's γ-Secretase:  Implications for Inhibitor Design
  作者：Chad L. Moore、Dartha D. Leatherwood、Thekla S. Diehl、Dennis J. Selkoe、Michael S. Wolfe

  DOI：10.1021/jm000100f

  日期：2000.9.1

  implicated in the etiology of Alzheimer's disease, is proteolysis within the transmembrane region of the amyloid precursor protein (APP) by gamma-secretase. Although considered an important target for therapeutic design, gamma-secretase has been neither well-characterized nor definitively identified. Previous studies in our laboratory using substrate-based difluoro ketone and difluoro alcohol transition-state

  与阿尔茨海默氏病的病因有关的淀粉样β蛋白（Abeta）的生成的最后一步是通过γ-分泌酶在淀粉样前体蛋白（APP）的跨膜区域内进行蛋白水解。尽管γ-分泌酶被认为是治疗设计的重要目标，但尚未被充分表征或确定。我们实验室中先前使用基于底物的二氟酮和二氟醇过渡态类似物抑制剂的研究表明，γ-分泌酶是天冬氨酰蛋白酶，具有宽松的序列特异性。为了进一步表征γ-分泌酶的活性位点，我们制备了一系列在P1位置具有不同空间体积的二氟酮肽类似物，并测试了这些化合物抑制APP转染细胞中Abeta产生的能力。庞大的脂肪族P1侧链（如仲丁基或环己基甲基）的引入导致增加的γ-分泌酶抑制能力，这表明一个大的S1口袋可容纳这些取代基，并为松散的序列特异性提供了进一步的证据。环己基甲基P1取代基可将N端截短为低分子量化合物（<600 Da），该化合物有效地阻断了Abeta的产生（IC（50）约为5 microM）。该发现表明，最
• Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors
  作者：Annette M. Doherty、Ila Sircar、Brian E. Kornberg、John Quin、R. Thomas Winters、James S. Kaltenbronn、Michael D. Taylor、Brian L. Batley、Stephen R. Rapundalo

  DOI：10.1021/jm00079a001

  日期：1992.1

  A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, Which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.