<(β-benzylthio)-β,β-pentamethylenepropionyl>-D-Tyr(Et)-Phe-Val-Asn-Cys(Bzl)-NH(CH2)2NH-Z-Gly | 143346-71-8

• 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: <(β-benzylthio)-β,β-pentamethylenepropionyl>-D-Tyr(Et)-Phe-Val-Asn-Cys(Bzl)-NH(CH2)2NH-Z-Gly
• 英文别名: [(β-benzylthio)-β,β-pentamethylenepropionyl]-D-Tyr(Et)-Phe-Val-Asn-Cys(Bzl)-NH(CH2)2NH-Z-Gly；benzyl N-[2-[2-[[(2R)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[2-(1-benzylsulfanylcyclohexyl)acetyl]amino]-3-(4-ethoxyphenyl)propanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-oxobutanoyl]amino]-3-benzylsulfanylpropanoyl]amino]ethylamino]-2-oxoethyl]carbamate
• CAS: 143346-71-8
• 化学式: C₆₆H₈₃N₉O₁₁S₂
• 分子量: 1242.57
• InChiKey: PYSPFQVLDWCOOT-LADGUQQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  88
• 可旋转键数：
  36
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  345
• 氢给体数：
  9
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  <(β-benzylthio)-β,β-pentamethylenepropionyl>-D-Tyr(Et)-Phe-Val-Asn-Cys(Bzl)-NH(CH2)2NH-Z-Gly 在 ammonium hydroxide 、 sodium 、 potassium hexacyanoferrate(III) 作用下， 生成 <(β-mercapto-β,β-pentamethylenepropionyl)>D-Tyr(Et)-Phe-Val-Asn-Cys-NH(CH2)2NH-Gly
  参考文献：
  名称：

  Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids

  摘要：

  We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-0-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antidiuretic (V2-receptor) and of the vasopressor (V1a-receptor) responses to arginine-vasopressin (AVP). Six of these peptides (1, 13, 17, 19, 2 1, and 23) have the Pro-Arg-Gly-NH2 tripeptide side chain fully or partially replaced or extended by ethylenediamine (Eda). The remaining 19 peptides have L- or D-amino acids retrolinked to these six C-terminal Eda peptides. Peptides 1, 13, 17, and 19 all have the ring structure of (A). Their side-chain structures are as follows: 1, Eda; 13, Pro-Eda; 17, Pro-Arg-Eda; 19, Arg-Gly-Eda. Peptide 21 is the Pro-Arg-Eda analogue of D; peptide 23 is the Pro-Arg-Gly-Eda analogue of E. Peptide 2 is the retro-Arg analogue of 1. Its side-chain structure is Eda<--Arg. Peptides 3-6 are analogues of 2 which have the D-Tyr-(Et)2 residue replaced by L-Tyr(Et)2 (3), D-Phe2 (4), D-Ile2 (5), or D-Leu2 (6), respectively. Peptides 7-12 are analogues of 2 which have the C-terminal retro-Arg replaced in retrofashion by D-Arg (7), Gly (8), Orn (9), D-Orn (10), D-Lys (11), or Arg-Arg (12). Peptides 14-16 have D-Orn (14), D-Lys (15), and D-Arg (16) retrosubstituted to peptide 13. Peptides 18, 20, and 22 are the retro-Arg-substituted analogues of 17, 19, and 21, respectively. Peptides 24 and 25 have Val and D-Val in retrolinkage with 23, respectively. All 25 peptides were examined for agonistic and antagonistic potencies in AVP V2/V1a assays. With the exception of peptides 5 and 6, all exhibit potent anti-V1a antagonism, with anti-V1a pA2 values in the range 7.64-8.33. Peptides 1-25 exhibit the following anti-V2 pA2 values: 1, 7.07 +/- 0.05; 2, 7.54 +/- 0.10; 3, 6.39 +/- 0.04; 4, 6.91 +/- 0.06; 5, approximately 5.8; 6, < 5.5; 7, 7.95 +/- 0.10; 8, 6.59 +/- 0.02; 9, 7.55 +/- 0.03; 10, 7.24 +/- 0.05; 11, 7.76 +/- 0.07; 12, 7.61 +/- 0.09; 13, 7.64 +/- 0.07; 14, 7.92 +/- 0.05; 15, 7.78 +/- 0.09; 16, 7.92 +/- 0.05; 17, 7.79 +/- 0.04; 18, 7.68 +/- 0.06; 19, 8.03 +/- 0.08; 20, 7.87 +/- 0.05; 21, 8.00 +/- 0.12; 22, 8.10 +/- 0.09; 23, 8.10 +/- 0.10; 24, 8.10 +/- 0.08; 25, 8.09 +/- 0.09. Comparison of the anti-V2 potencies of peptides 1-6 clearly shows the superiority of the D-Tyr(Et)2 substitution in leading to retention and enhancement Of V2 antagonism in this series. With only one exception (peptide 8), the retromodified peptides exhibit either full retention and in a number of cases (2, 7, 9-12, 14, and 16) a 1.5-7.5-fold enhancement of V2 antagonism compared to their respective parent C-terminal Eda peptides. The retro-Arg-substituted Ile4 peptide 22 exhibits a 2-fold enhancement of anti-V2 potency relative to its Val4 counterpart 18. The retromodified peptides 24 and 25, which possess extensions at the C-terminal, also exhibit good retention of V2 antagonism. Many of these retrosubstituted peptides are as potent as the most potent V2 antagonists reported to date. Some of these may be orally active. These findings point to the usefulness of Eda retromodifications in the design of AVP antagonists. Furthermore they provide useful clues to the design of (a) more potent and selective AVP antagonists and (b) novel photoaffinity and radioiodinated ligands as probes of AVP receptors.

  DOI：

  10.1021/jm00099a018
• 作为产物：
  描述：

  BOC-L-苯丙氨酸 在 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 反应 19.0h， 生成 <(β-benzylthio)-β,β-pentamethylenepropionyl>-D-Tyr(Et)-Phe-Val-Asn-Cys(Bzl)-NH(CH2)2NH-Z-Gly
  参考文献：
  名称：

  Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids

  摘要：

  We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-0-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antidiuretic (V2-receptor) and of the vasopressor (V1a-receptor) responses to arginine-vasopressin (AVP). Six of these peptides (1, 13, 17, 19, 2 1, and 23) have the Pro-Arg-Gly-NH2 tripeptide side chain fully or partially replaced or extended by ethylenediamine (Eda). The remaining 19 peptides have L- or D-amino acids retrolinked to these six C-terminal Eda peptides. Peptides 1, 13, 17, and 19 all have the ring structure of (A). Their side-chain structures are as follows: 1, Eda; 13, Pro-Eda; 17, Pro-Arg-Eda; 19, Arg-Gly-Eda. Peptide 21 is the Pro-Arg-Eda analogue of D; peptide 23 is the Pro-Arg-Gly-Eda analogue of E. Peptide 2 is the retro-Arg analogue of 1. Its side-chain structure is Eda<--Arg. Peptides 3-6 are analogues of 2 which have the D-Tyr-(Et)2 residue replaced by L-Tyr(Et)2 (3), D-Phe2 (4), D-Ile2 (5), or D-Leu2 (6), respectively. Peptides 7-12 are analogues of 2 which have the C-terminal retro-Arg replaced in retrofashion by D-Arg (7), Gly (8), Orn (9), D-Orn (10), D-Lys (11), or Arg-Arg (12). Peptides 14-16 have D-Orn (14), D-Lys (15), and D-Arg (16) retrosubstituted to peptide 13. Peptides 18, 20, and 22 are the retro-Arg-substituted analogues of 17, 19, and 21, respectively. Peptides 24 and 25 have Val and D-Val in retrolinkage with 23, respectively. All 25 peptides were examined for agonistic and antagonistic potencies in AVP V2/V1a assays. With the exception of peptides 5 and 6, all exhibit potent anti-V1a antagonism, with anti-V1a pA2 values in the range 7.64-8.33. Peptides 1-25 exhibit the following anti-V2 pA2 values: 1, 7.07 +/- 0.05; 2, 7.54 +/- 0.10; 3, 6.39 +/- 0.04; 4, 6.91 +/- 0.06; 5, approximately 5.8; 6, < 5.5; 7, 7.95 +/- 0.10; 8, 6.59 +/- 0.02; 9, 7.55 +/- 0.03; 10, 7.24 +/- 0.05; 11, 7.76 +/- 0.07; 12, 7.61 +/- 0.09; 13, 7.64 +/- 0.07; 14, 7.92 +/- 0.05; 15, 7.78 +/- 0.09; 16, 7.92 +/- 0.05; 17, 7.79 +/- 0.04; 18, 7.68 +/- 0.06; 19, 8.03 +/- 0.08; 20, 7.87 +/- 0.05; 21, 8.00 +/- 0.12; 22, 8.10 +/- 0.09; 23, 8.10 +/- 0.10; 24, 8.10 +/- 0.08; 25, 8.09 +/- 0.09. Comparison of the anti-V2 potencies of peptides 1-6 clearly shows the superiority of the D-Tyr(Et)2 substitution in leading to retention and enhancement Of V2 antagonism in this series. With only one exception (peptide 8), the retromodified peptides exhibit either full retention and in a number of cases (2, 7, 9-12, 14, and 16) a 1.5-7.5-fold enhancement of V2 antagonism compared to their respective parent C-terminal Eda peptides. The retro-Arg-substituted Ile4 peptide 22 exhibits a 2-fold enhancement of anti-V2 potency relative to its Val4 counterpart 18. The retromodified peptides 24 and 25, which possess extensions at the C-terminal, also exhibit good retention of V2 antagonism. Many of these retrosubstituted peptides are as potent as the most potent V2 antagonists reported to date. Some of these may be orally active. These findings point to the usefulness of Eda retromodifications in the design of AVP antagonists. Furthermore they provide useful clues to the design of (a) more potent and selective AVP antagonists and (b) novel photoaffinity and radioiodinated ligands as probes of AVP receptors.

  DOI：

  10.1021/jm00099a018

文献信息

• Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids
  作者：Maurice Manning、Jozef Przybylski、Zbigniew Grzonka、Eleonora Nawrocka、Bernard Lammek、Aleksandra Misicka、Ling Ling Cheng、W. Y. Chan、Nga Ching Wo、Wilbur H. Sawyer

  DOI：10.1021/jm00099a018

  日期：1992.10

  We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-0-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antidiuretic (V2-receptor) and of the vasopressor (V1a-receptor) responses to arginine-vasopressin (AVP). Six of these peptides (1, 13, 17, 19, 2 1, and 23) have the Pro-Arg-Gly-NH2 tripeptide side chain fully or partially replaced or extended by ethylenediamine (Eda). The remaining 19 peptides have L- or D-amino acids retrolinked to these six C-terminal Eda peptides. Peptides 1, 13, 17, and 19 all have the ring structure of (A). Their side-chain structures are as follows: 1, Eda; 13, Pro-Eda; 17, Pro-Arg-Eda; 19, Arg-Gly-Eda. Peptide 21 is the Pro-Arg-Eda analogue of D; peptide 23 is the Pro-Arg-Gly-Eda analogue of E. Peptide 2 is the retro-Arg analogue of 1. Its side-chain structure is Eda<--Arg. Peptides 3-6 are analogues of 2 which have the D-Tyr-(Et)2 residue replaced by L-Tyr(Et)2 (3), D-Phe2 (4), D-Ile2 (5), or D-Leu2 (6), respectively. Peptides 7-12 are analogues of 2 which have the C-terminal retro-Arg replaced in retrofashion by D-Arg (7), Gly (8), Orn (9), D-Orn (10), D-Lys (11), or Arg-Arg (12). Peptides 14-16 have D-Orn (14), D-Lys (15), and D-Arg (16) retrosubstituted to peptide 13. Peptides 18, 20, and 22 are the retro-Arg-substituted analogues of 17, 19, and 21, respectively. Peptides 24 and 25 have Val and D-Val in retrolinkage with 23, respectively. All 25 peptides were examined for agonistic and antagonistic potencies in AVP V2/V1a assays. With the exception of peptides 5 and 6, all exhibit potent anti-V1a antagonism, with anti-V1a pA2 values in the range 7.64-8.33. Peptides 1-25 exhibit the following anti-V2 pA2 values: 1, 7.07 +/- 0.05; 2, 7.54 +/- 0.10; 3, 6.39 +/- 0.04; 4, 6.91 +/- 0.06; 5, approximately 5.8; 6, < 5.5; 7, 7.95 +/- 0.10; 8, 6.59 +/- 0.02; 9, 7.55 +/- 0.03; 10, 7.24 +/- 0.05; 11, 7.76 +/- 0.07; 12, 7.61 +/- 0.09; 13, 7.64 +/- 0.07; 14, 7.92 +/- 0.05; 15, 7.78 +/- 0.09; 16, 7.92 +/- 0.05; 17, 7.79 +/- 0.04; 18, 7.68 +/- 0.06; 19, 8.03 +/- 0.08; 20, 7.87 +/- 0.05; 21, 8.00 +/- 0.12; 22, 8.10 +/- 0.09; 23, 8.10 +/- 0.10; 24, 8.10 +/- 0.08; 25, 8.09 +/- 0.09. Comparison of the anti-V2 potencies of peptides 1-6 clearly shows the superiority of the D-Tyr(Et)2 substitution in leading to retention and enhancement Of V2 antagonism in this series. With only one exception (peptide 8), the retromodified peptides exhibit either full retention and in a number of cases (2, 7, 9-12, 14, and 16) a 1.5-7.5-fold enhancement of V2 antagonism compared to their respective parent C-terminal Eda peptides. The retro-Arg-substituted Ile4 peptide 22 exhibits a 2-fold enhancement of anti-V2 potency relative to its Val4 counterpart 18. The retromodified peptides 24 and 25, which possess extensions at the C-terminal, also exhibit good retention of V2 antagonism. Many of these retrosubstituted peptides are as potent as the most potent V2 antagonists reported to date. Some of these may be orally active. These findings point to the usefulness of Eda retromodifications in the design of AVP antagonists. Furthermore they provide useful clues to the design of (a) more potent and selective AVP antagonists and (b) novel photoaffinity and radioiodinated ligands as probes of AVP receptors.