(S,S)-γ-amino-β-hydroxy-N-<2-(4-morpholinyl)ethyl>cyclohexane pentanamide | 124278-65-5

• 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: (S,S)-γ-amino-β-hydroxy-N-<2-(4-morpholinyl)ethyl>cyclohexane pentanamide
• 英文别名: (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-N-(2-morpholin-4-ylethyl)pentanamide
• CAS: 124278-65-5
• 化学式: C₁₇H₃₃N₃O₃
• 分子量: 327.467
• InChiKey: CAMANUYYUUHACC-HOTGVXAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  87.8
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S,S)-γ-amino-β-hydroxy-N-<2-(4-morpholinyl)ethyl>cyclohexane pentanamide 在 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 17.17h， 生成 N-[(2S,3S)-1-cyclohexyl-3-hydroxy-5-(2-morpholin-4-ylethylamino)-5-oxopentan-2-yl]-6-formamido-2-[[3-naphthalen-1-yl-2-(naphthalen-1-ylmethyl)propanoyl]amino]hex-4-ynamide
  参考文献：
  名称：

  新的人类肾素抑制剂，在P2位点含有新的替代物。

  摘要：

  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

  DOI：

  10.1021/jm00108a004
• 作为产物：
  描述：

  (4S)-40<(tertibutyloxycarbonyl)amino>-3-oxo-5-phenylpentanoic acid ethyl ester 在 [(R)-BINAP]RuBr₂ 、 rhodium on alumina 盐酸 、 氢氧化钾 、 氢气 、 三乙胺 、 焦碳酸二乙酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 为溶剂， 25.0 ℃ 、10.13 MPa 条件下， 反应 175.5h， 生成 (S,S)-γ-amino-β-hydroxy-N-<2-(4-morpholinyl)ethyl>cyclohexane pentanamide
  参考文献：
  名称：

  含有他汀类似物的肾素抑制剂的合成和生物学活性。

  摘要：

  描述了含有他汀类似物的二肽肾素抑制剂的合成和生物学活性。二肽肾素抑制剂的合成方法的关键步骤是2（R）取代的3-氨基羰基丙酸的不对称合成和（3S，4S）-他汀类似物的非对映选择性合成。这些抑制剂（2,14-40）在3-140 nM范围内抑制人肾素。发现抑制剂ES 6864（2）是人肾素的高效抑制剂（IC50：4.6 x 10（-9）M），并显示出高的酶特异性。口服给予3 mg / kg的ES 6864到有意识的贫钠mos猴1小时后对血浆肾素活性（PRA）的抑制超过80％。

  DOI：

  10.1248/cpb.38.103

文献信息

• Renin inhibitors containing .alpha.-heteroatom amino acids as P2 residues
  作者：Joseph T. Repine、James S. Kaltenbronn、Annette M. Doherty、James M. Hamby、Richard J. Himmelsbach、Brian E. Kornberg、Michael D. Taylor、ELizabeth A. Lunney、Christine Humblet

  DOI：10.1021/jm00084a008

  日期：1992.3

  A series of renin inhibitors having alpha-heteroatom amino acids as P2 substitutions has been prepared. Examples where the heteroatom is oxygen, sulfur, or nitrogen are described. Many of the compounds exhibit subnanomolar potency when tested in vitro against monkey renin. When selected compounds were tested orally in conscious, salt-depleted, normotensive, Cynomolgus monkeys, low to moderate blood

  已经制备了一系列具有α-杂原子氨基酸作为P2取代的肾素抑制剂。描述了杂原子为氧，硫或氮的实例。在体外针对猴肾素进行测试时，许多化合物均表现出亚纳摩尔效价。当在有意识的，盐分稀少，血压正常的食蟹猴中对选定的化合物进行口服测试时，观察到低至中度的血压降低。在口服剂量为30 mg / kg时，化合物53a在给药后2.5小时最大降低了18 mmHg的血压。
• Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors
  作者：William C. Patt、Harriet W. Hamilton、Michael D. Taylor、Michael J. Ryan、David G. Taylor、Cleo J. C. Connolly、Annette M. Doherty、Sylvester R. Klutchko、Ila Sircar

  DOI：10.1021/jm00092a006

  日期：1992.7

  A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.
• Renin inhibitors containing esters at the P2-position. Oral activity in a derivative of methyl aminomalonate
  作者：Joseph T. Repine、Richard J. Himmelsbach、John C. Hodges、James S. Kaltenbronn、Ila Sircar、Richard W. Skeean、Sean T. Brennan、Timothy R. Hurley、Elizabeth Lunney

  DOI：10.1021/jm00111a002

  日期：1991.7

  A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 < 2 min). Fractional crystallization was employed to obtain the individual diastereomers in > 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.
• Klutchko, Sylvester; O'Brien, Patrick; Hodges, John C., Synthetic Communications, 1989, vol. 19, # 13-14, p. 2573 - 2584
  作者：Klutchko, Sylvester、O'Brien, Patrick、Hodges, John C.

  DOI：——

  日期：——
• KLUTCHKO, SYLVESTER;OBRIEN, PATRICK;HODGES, JOHN C., SYNTH. COMMUN., 19,(1989) N3-14, C. 2573-2583
  作者：KLUTCHKO, SYLVESTER、OBRIEN, PATRICK、HODGES, JOHN C.

  DOI：——

  日期：——