(2S,5R)-1-[2-((S)-2-Acetylsulfanyl-3-phenyl-propionylamino)-acetyl]-5-(2-hydroxy-phenyl)-pyrrolidine-2-carboxylic acid ethyl ester | 177742-00-6

• 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: (2S,5R)-1-[2-((S)-2-Acetylsulfanyl-3-phenyl-propionylamino)-acetyl]-5-(2-hydroxy-phenyl)-pyrrolidine-2-carboxylic acid ethyl ester
• 英文别名: ethyl (2S,5R)-1-[2-[[(2S)-2-acetylsulfanyl-3-phenylpropanoyl]amino]acetyl]-5-(2-hydroxyphenyl)pyrrolidine-2-carboxylate
• CAS: 177742-00-6
• 化学式: C₂₆H₃₀N₂O₆S
• 分子量: 498.6
• InChiKey: JTHMTYSMGOJSDH-GIWBLDEGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  138
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (2S,5R)-1-[2-((S)-2-Acetylsulfanyl-3-phenyl-propionylamino)-acetyl]-5-(2-hydroxy-phenyl)-pyrrolidine-2-carboxylic acid ethyl ester 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以93%的产率得到(2S,5R)-5-(2-Hydroxy-phenyl)-1-[2-((S)-2-mercapto-3-phenyl-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid
  参考文献：
  名称：

  Design of Orally Active Dual Inhibitors of Neutral Endopeptidase and Angiotensin-Converting Enzyme with Long Duration of Action

  摘要：

  Mercaptoacyl dipeptides, containing a glycine Linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournie-Zaluski, M. C.; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S-1, S-1', and S-2' subsites of this enzyme, (ii) and to interact with the S-1' and S-2' subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P.; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decreasein ACE inhibition. This shows that, in agreement with molecular modeling studies, a steric constraint as weak as a methyl group hinders optimal ACE active site recognition, Among these compounds, the dual inhibitor 26 (RB 106) (K-i, ACE =: 0.35 nM; NEP = 1.6 nM) showed excellent pharmacokinetic properties with an almost complete in vivo inhibition of NEP and ACE for more than 4 h after oral administration in mice of a low dose (2.6 x 10(-5) mol/kg) of the inhibitor. Moreover, RE 106 remained active 12 h after oral administration In spontaneous hypertensive rats, a chronic treatment of orally administered RB 106 (25 mg/kg/day) induced a prolonged hypotensive effect (-28 mmHg) still significant 2 days after the end of the treatment. In DOCA salt rats, a hypotensive response and a significant natriuresis were observed after iv administration RE 106, which is one of the most potent dual inhibitors described to date, could have interesting clinical applications in long term treatment of congestive heart failure and myocardial ischemia.

  DOI：

  10.1021/jm950783c
• 作为产物：
  描述：

  (S)-5-(2-Hydroxy-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester 在 platinum(IV) oxide 、 palladium on activated charcoal 盐酸 、 三聚氯氰 、 氢气 、 1-羟基苯并三唑 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 为溶剂， 25.0 ℃ 、3.0 MPa 条件下， 反应 4.0h， 生成 (2S,5R)-1-[2-((S)-2-Acetylsulfanyl-3-phenyl-propionylamino)-acetyl]-5-(2-hydroxy-phenyl)-pyrrolidine-2-carboxylic acid ethyl ester
  参考文献：
  名称：

  Design of Orally Active Dual Inhibitors of Neutral Endopeptidase and Angiotensin-Converting Enzyme with Long Duration of Action

  摘要：

  Mercaptoacyl dipeptides, containing a glycine Linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournie-Zaluski, M. C.; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S-1, S-1', and S-2' subsites of this enzyme, (ii) and to interact with the S-1' and S-2' subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P.; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decreasein ACE inhibition. This shows that, in agreement with molecular modeling studies, a steric constraint as weak as a methyl group hinders optimal ACE active site recognition, Among these compounds, the dual inhibitor 26 (RB 106) (K-i, ACE =: 0.35 nM; NEP = 1.6 nM) showed excellent pharmacokinetic properties with an almost complete in vivo inhibition of NEP and ACE for more than 4 h after oral administration in mice of a low dose (2.6 x 10(-5) mol/kg) of the inhibitor. Moreover, RE 106 remained active 12 h after oral administration In spontaneous hypertensive rats, a chronic treatment of orally administered RB 106 (25 mg/kg/day) induced a prolonged hypotensive effect (-28 mmHg) still significant 2 days after the end of the treatment. In DOCA salt rats, a hypotensive response and a significant natriuresis were observed after iv administration RE 106, which is one of the most potent dual inhibitors described to date, could have interesting clinical applications in long term treatment of congestive heart failure and myocardial ischemia.

  DOI：

  10.1021/jm950783c

文献信息

• Design of Orally Active Dual Inhibitors of Neutral Endopeptidase and Angiotensin-Converting Enzyme with Long Duration of Action
  作者：Marie-Claude Fournie-Zaluski、Pascale Coric、Vincent Thery、Walter Gonzalez、Hervé Meudal、Serge Turcaud、Jean-Baptiste Michel、Bernard P. Roques

  DOI：10.1021/jm950783c

  日期：1996.1.1

  Mercaptoacyl dipeptides, containing a glycine Linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournie-Zaluski, M. C.; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S-1, S-1', and S-2' subsites of this enzyme, (ii) and to interact with the S-1' and S-2' subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P.; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decreasein ACE inhibition. This shows that, in agreement with molecular modeling studies, a steric constraint as weak as a methyl group hinders optimal ACE active site recognition, Among these compounds, the dual inhibitor 26 (RB 106) (K-i, ACE =: 0.35 nM; NEP = 1.6 nM) showed excellent pharmacokinetic properties with an almost complete in vivo inhibition of NEP and ACE for more than 4 h after oral administration in mice of a low dose (2.6 x 10(-5) mol/kg) of the inhibitor. Moreover, RE 106 remained active 12 h after oral administration In spontaneous hypertensive rats, a chronic treatment of orally administered RB 106 (25 mg/kg/day) induced a prolonged hypotensive effect (-28 mmHg) still significant 2 days after the end of the treatment. In DOCA salt rats, a hypotensive response and a significant natriuresis were observed after iv administration RE 106, which is one of the most potent dual inhibitors described to date, could have interesting clinical applications in long term treatment of congestive heart failure and myocardial ischemia.