(1S,2R)-<1-(cyclohexylmethyl)-3,3-difluoro-4-<<2-(4-morpholino)ethyl>amino>-2-hydroxy-4-oxobutyl>amine | 134334-91-1

• 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: (1S,2R)-<1-(cyclohexylmethyl)-3,3-difluoro-4-<<2-(4-morpholino)ethyl>amino>-2-hydroxy-4-oxobutyl>amine
• 英文别名: (1S,2R)-(1-(cyclohexylmethyl)-3,3-difluoro-4-{[2-(4-morpholino)ethyl]amino}-2-hydroxy-4-oxobutyl)amine
• CAS: 134334-91-1
• 化学式: C₁₇H₃₁F₂N₃O₃
• 分子量: 363.448
• InChiKey: WBIPUBXMGFESRT-LSDHHAIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.73
• 重原子数：
  25.0
• 可旋转键数：
  8.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  87.82
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (1S,2R)-<1-(cyclohexylmethyl)-3,3-difluoro-4-<<2-(4-morpholino)ethyl>amino>-2-hydroxy-4-oxobutyl>amine 在 盐酸 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 35.25h， 生成 3-<<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydoxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>-N--3-oxo-DL-alanine methyl ester
  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：

  (3R,4S)-5-cyclohexyl-2,2-difluoro-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic 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 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 (1S,2R)-<1-(cyclohexylmethyl)-3,3-difluoro-4-<<2-(4-morpholino)ethyl>amino>-2-hydroxy-4-oxobutyl>amine
  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

• 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。
• 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.