methyl <1S-(1R*,2S*,3R*)>-3-<<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>amino>-N--3-oxo-DL-alaninate | 127953-03-1

• 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: methyl <1S-(1R*,2S*,3R*)>-3-<<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>amino>-N--3-oxo-DL-alaninate
• 英文别名: <1S-(1R^*,2S^*,3R^*)>-3-<<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>amino>-N--3-oxo-DL-alanine methyl ester；PD 132002；methyl 3-{[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino}-2-({(2S)-2-[(4-morpholinylsulfonyl)amino]-3-phenylpropanoyl}amino)-3-oxopropanoate；methyl 3-[[(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]amino]-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]-3-oxopropanoate
• CAS: 127953-03-1；134452-03-2；134452-04-3；142185-72-6
• 化学式: C₃₁H₅₀N₄O₉S
• 分子量: 654.825
• InChiKey: IEWAGORIVPFRDB-KDPBSHNGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  45
• 可旋转键数：
  17
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  192
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  methyl <1S-(1R*,2S*,3R*)>-3-<<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>amino>-N--3-oxo-DL-alaninate 在 sodium hydroxide 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 乙醚 为溶剂， 生成 <1S-(1R^*,2S^*,3R^*)>-3-<<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>amino>-N--3-oxo-DL-alanine isopropyl 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
• 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 2.0h， 生成 methyl <1S-(1R*,2S*,3R*)>-3-<<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>amino>-N--3-oxo-DL-alaninate
  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：——