N-(4-morpholinylsulfonyl)-L-phenylalanyl-N-<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>-N-6-<(methylamino)thioxomethyl>-L-lysinamide | 132101-82-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: N-(4-morpholinylsulfonyl)-L-phenylalanyl-N-<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>-N-6-<(methylamino)thioxomethyl>-L-lysinamide
• 英文别名: (2S)-N-[(2S,3R)-1-cyclohexyl-4,4-difluoro-3-hydroxy-5-(2-morpholin-4-ylethylamino)-5-oxopentan-2-yl]-6-(methylcarbamothioylamino)-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]hexanamide
• CAS: 132101-82-7
• 化学式: C₃₈H₆₂F₂N₈O₈S₂
• 分子量: 861.088
• InChiKey: FYHDUDNCHVCGMS-ZWDYZTTJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.41
• 重原子数：
  58.0
• 可旋转键数：
  22.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  202.7
• 氢给体数：
  7.0
• 氢受体数：
  10.0

反应信息

• 作为产物：
  描述：

  {(S)-5-[(1S,2R)-1-Cyclohexylmethyl-3,3-difluoro-2-hydroxy-3-(2-morpholin-4-yl-ethylcarbamoyl)-propylcarbamoyl]-5-[(S)-2-(morpholine-4-sulfonylamino)-3-phenyl-propionylamino]-pentyl}-carbamic acid benzyl ester 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 24.0h， 生成 N-(4-morpholinylsulfonyl)-L-phenylalanyl-N-<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>-N-6-<(methylamino)thioxomethyl>-L-lysinamide
  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

文献信息

• New inhibitors of human renin that contain novel replacements at the P2 site
  作者：Annette M. Doherty、James S. Kaltenbronn、James P. Hudspeth、Joseph T. Repine、William H. Roark、Ila Sircar、Frank J. Tinney、Cleo J. Connolly、John C. Hodges

  DOI：10.1021/jm00108a004

  日期：1991.4

  for renin over cathepsin D by correct modification at the P2' and P1-P1' sites. Variations at the P4 site have been utilized to lower the log P values of these renin inhibitors while maintaining high potency. Compound 42, which exhibited an IC50 of 3.70 nM, log P of 2.3, and showed high specificity for renin, was selected for further studies. It was found to be very stable under neutral, acidic, and

  已经制备了一系列在P2位点具有新修饰的肾素抑制剂。结构-活性关系显示，对于特定的P2片段，除P1-P1'基团外，体外效能还高度依赖于P2'部分的性质。尽管P2侧链中的不饱和度不是特别重要，但已发现P2侧链的长度和ε-NP2取代的选择对体外效能很重要。分子模型研究表明，P2侧链可能与P2'结合位点发生不利相互作用。通过在P2'和P1-P1'位进行正确的修饰，可以控制肾素对组织蛋白酶D的特异性。已经利用P4位点的变化来降低这些肾素抑制剂的log P值，同时保持高效力。选择化合物42，其IC50为3.70 nM，log P为2.3，并且对肾素显示出高特异性，用于进一步研究。发现它在中性，酸性和碱性条件下非常稳定。在模拟肠液中，化合物42的半衰期为37分钟，而4小时后实际上不受模拟胃液的影响。化合物42在静脉内施用给贫盐的正常血压食蟹猴后产生明显的降压反应。和基本条件。在模拟肠液中，化合物42的半
• DOHERTY, ANNETTE M.;KALTENBRONN, JAMES S.;HUDSPETH, JAMES P.;REPINE, JOSE+, J. MED. CHEM., 34,(1991) N, C. 1258-1271
  作者：DOHERTY, ANNETTE M.、KALTENBRONN, JAMES S.、HUDSPETH, JAMES P.、REPINE, JOSE+

  DOI：——

  日期：——