*,R^*)>-3-<<1-(cyclohexylmethyl)-2-hydroxy-4<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>-N--3-oxo-DL-alanine methyl ester | 124278-25-7

• 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: *,R^*)>-3-<<1-(cyclohexylmethyl)-2-hydroxy-4<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>-N--3-oxo-DL-alanine methyl ester
• 英文别名: methyl 3-[[(2S,3S)-1-cyclohexyl-3-hydroxy-5-(2-morpholin-4-ylethylamino)-5-oxopentan-2-yl]amino]-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]-3-oxopropanoate
• CAS: 124278-25-7；134452-06-5
• 化学式: C₃₄H₅₄N₆O₁₀S
• 分子量: 738.903
• InChiKey: NMIWPNMFASWALT-SJTZDSSUSA-N

物化性质

• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  51
• 可旋转键数：
  19
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  213
• 氢给体数：
  5
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  N-(4-MorpholinYlsulfonyl)-L-phenylalanine 在 palladium on activated charcoal 氢气 、 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 5.0h， 生成 *,R^*)>-3-<<1-(cyclohexylmethyl)-2-hydroxy-4<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>-N--3-oxo-DL-alanine methyl ester
  参考文献：
  名称：

  Renin inhibitors containing esters at the P2-position. Oral activity in a derivative of methyl aminomalonate

  摘要：

  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.

  DOI：

  10.1021/jm00111a002

文献信息

• REPINE, JOSEPH T.;HIMMELSBACH, RICHARD J.;HODGES, JOHN C.;KALTENBRONN, JA+, J. MED. CHEM., 34,(1991) N, C. 1935-1943
  作者：REPINE, JOSEPH T.、HIMMELSBACH, RICHARD J.、HODGES, JOHN C.、KALTENBRONN, JA+

  DOI：——

  日期：——
• 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.