(2S)-2-[(4S,5S)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl-N-butyl-3-methylbutanamide | 105852-65-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S)-2-[(4S,5S)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl-N-butyl-3-methylbutanamide
• 英文别名: benzyl (4S,5S)-5-[(2S)-2-(butylcarbamoyl)-3-methylbutyl]-4-(cyclohexylmethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
• CAS: 105852-65-1
• 化学式: C₃₀H₄₈N₂O₄
• 分子量: 500.722
• InChiKey: MBCTVXDELVRDRK-QKDODKLFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S)-2-[(4S,5S)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl-N-butyl-3-methylbutanamide 在 palladium on activated charcoal 氢气 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.5h， 生成 (2S,4S,5S)-5-[(S)-2-[(S)-2-Benzyl-3-(2-methyl-propane-2-sulfonyl)-propionylamino]-3-(1H-imidazol-4-yl)-propionylamino]-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid butylamide
  参考文献：
  名称：

  Synthesis and biological activity of some transition-state inhibitors of human renin

  摘要：

  A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.

  DOI：

  10.1021/jm00117a027
• 作为产物：
  描述：

  异戊酸 在 六甲基磷酰三胺 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 (2S)-2-[(4S,5S)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl-N-butyl-3-methylbutanamide
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives

  摘要：

  A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

  DOI：

  10.1021/jm00171a006

文献信息

• 5-(heterocyclylalkanoyl)amino-4-hydroxypentanamides
  申请人：Imperial Chemical Industries plc

  公开号：US05091425A1

  公开（公告）日：1992-02-25

  This invention concerns novel nitrogen derivatives of the formula I ##STR1## (and their pharmaceutically-acceptable salts), together with pharmaceutical compositions containing them. The nitrogen derivatives are inhibitors of the catalytic action of renin. The invention further concerns novel processes for the manufacture of said inhibitors.

  这项发明涉及公式I的新颖氮衍生物##STR1##（及其药用盐），以及含有它们的药物组合物。这些氮衍生物是肾素催化作用的抑制剂。该发明还涉及制造上述抑制剂的新型工艺。
• BRADBURY, ROBERT H.;MAJOR, JOHN S.;OLDHAM, ALEC A.;RIVETT, JANET E.;ROBER+, J. MED. CHEM., 33,(1990) N, C. 2335-2342
  作者：BRADBURY, ROBERT H.、MAJOR, JOHN S.、OLDHAM, ALEC A.、RIVETT, JANET E.、ROBER+

  DOI：——

  日期：——
• US5091425A
  申请人：——

  公开号：US5091425A

  公开（公告）日：1992-02-25
• 1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives
  作者：Robert H. Bradbury、John S. Major、Alec A. Oldham、Janet E. Rivett、David A. Roberts、Anthony M. Slater、David Timms、David Waterson

  DOI：10.1021/jm00171a006

  日期：1990.9

  A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.
• Synthesis and biological activity of some transition-state inhibitors of human renin
  作者：Peter Buehlmayer、Anthony Caselli、Walter Fuhrer、Richard Goeschke、Vittorio Rasetti、Heinrich Rueger、James L. Stanton、Leoluca Criscione、Jeanette M. Wood

  DOI：10.1021/jm00117a027

  日期：1988.9

  A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.