N~5~-(二氨基甲亚基)-N~2~-甲基-D-鸟氨酰基-N-{(2S)-4-氨基-1-羧基-4-甲酰基-5-[(E)-亚氨基甲基]-3,7-二羰基-7-苯基庚烷-2-基}甘氨酸酰胺 | 153345-74-5

• 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
• 中文名称: N~5~-(二氨基甲亚基)-N~2~-甲基-D-鸟氨酰基-N-{(2S)-4-氨基-1-羧基-4-甲酰基-5-[(E)-亚氨基甲基]-3,7-二羰基-7-苯基庚烷-2-基}甘氨酸酰胺
• 英文名称: cyclo(D-Abu-N-MeArg-Gly-Asp-Mamb)
• 英文别名: DMP728；Cyclo((2R)-2-aminobutanoyl-N2-methyl-L-arginylglycyl-L-alpha-aspartyl-3-(aminomethyl)benzoyl)；2-[(5S,11S,14R)-11-[3-(diaminomethylideneamino)propyl]-14-ethyl-12-methyl-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentazabicyclo[15.3.1]henicosa-1(21),17,19-trien-5-yl]acetic acid
• CAS: 153345-74-5
• 化学式: C₂₅H₃₆N₈O₇
• 分子量: 560.61
• InChiKey: JWRYVLUXFOYZCH-SQNIBIBYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  40
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  238
• 氢给体数：
  7
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  甲烷磺酸 、 N~5~-(二氨基甲亚基)-N~2~-甲基-D-鸟氨酰基-N-{(2S)-4-氨基-1-羧基-4-甲酰基-5-[(E)-亚氨基甲基]-3,7-二羰基-7-苯基庚烷-2-基}甘氨酸酰胺 以 水 、 异丙醇 为溶剂， 以99%的产率得到(5R,11R,14R)-11-{3-[(二氨基亚甲基)氨基]丙基}-14-乙基-12-甲基-4,7,10,13,16-五氧代-3,6,9,12,15-戊氮杂双环[15.3.1]二十一-1(21),17,19-三烯-5-羧酸甲烷磺酸酯(1:1)
  参考文献：
  名称：

  An Efficient Synthesis of Cyclic RGD Peptides as Antithrombotic Agents

  摘要：

  DOI：

  10.1021/jo9603284
• 作为产物：
  描述：

  Boc-N-MeArg(Tos)-Gly-OBzl 在 palladium on activated charcoal 氢氟酸 、 氢气 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 苯甲醚 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.58h， 生成 N~5~-(二氨基甲亚基)-N~2~-甲基-D-鸟氨酰基-N-{(2S)-4-氨基-1-羧基-4-甲酰基-5-[(E)-亚氨基甲基]-3,7-二羰基-7-苯基庚烷-2-基}甘氨酸酰胺
  参考文献：
  名称：

  Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa

  摘要：

  Although peptides adopt a large ensemble of conformations in aqueous solution, they are generally believed to bind to a receptor in a unique conformation. Thus, there is considerable interest in devising methods to restrict the conformational freedom of peptides. One such approach involves tying the amino and carboxy terminal ends of the peptide onto a semirigid template that will lock the intervening peptide backbone into a single conformer or a family of related conformers. This general strategy has been tested using the tripeptide sequence Arg-Gly-Asp (RGD), which binds with low affinity to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa or alpha(IIb)beta(3)) Mimics of RGD are of interest as antithrombotics because of their ability to inhibit the aggregation of platelets. Prior to this study, other workers (Samanen et al. J. Med. Chem. 1991, 34, 3114-3125) prepared a disulfide-containing cyclic pentapeptide that bound to GPIIb/IIIa with an affinity of approximately 0.1 mu M. NMR analysis of the solution conformation of this peptide suggested that replacing the disulfide-containing portion of the cycle with the amino acid m-(aminomethyl)benzoic acid would lead to a more rigid structure. Indeed, introduction of this template into a cyclic ROD-containing peptide resulted in compounds with high affinity for the receptor. Further, systematic inclusion of additional conformational constraints in the form of N-alpha- and C-alpha-alkyl groups led to a peptide with an affinity of approximately 100 pM for binding to the receptor. This peptide also showed good activity in the platelet aggregation assay at oral doses as low as 0.1 mg/kg.

  DOI：

  10.1021/ja00087a007

文献信息

• An Efficient Synthesis of Glycoprotein IIb/IIIa Inhibitor DMP728. A Novel Synthesis of N.alpha.-Methylarginine-Containing Peptide
  作者：Chu-Biao Xue、William F. DeGrado

  DOI：10.1021/jo00109a027

  日期：1995.2

  An efficient synthesis of an antithrombotic cyclic peptide antagonist of glycoprotein IIb/IIIa, cycle(D-Abu-N-a-methyl-Arg-Gly-Asp-m-(aminomethyl)benzoic acid) has been developed. In the course of this work an efficient and selective method has been developed for the synthesis of derivatives of N-a-methylarginine from Cbz-Gln. The carboxamide of Cbz-Gln is dehydrated to the corresponding nitrile, and the resulting compound is methylated providing Cbz-2-(methylamino)-4-cyanobutyric acid, a diprotected precursor of N-a-methylornithine. At a later point in the reaction sequence the nitrile is reduced to the amine and the resulting N-a-methylornithine derivative is guanylated, converting it to a derivative of N-a-methylarginine.
• Alpha Helical Mimics, Their Uses and Methods For Their Production
  申请人：Fairlie David P.

  公开号：US20080242598A1

  公开（公告）日：2008-10-02

  This invention discloses short chain peptides that have been constrained to adopt an alpha helical conformation and their use as alpha helical scaffolds for directing amino acid side chains into positions analogous to those found in longer chain alpha helical peptides and for attaching peptidic or non-peptidic appendages in order to mimic side chains of longer alpha helical peptides. More particularly the invention discloses alpha helical cyclic pentapeptides and their use as alpha helical scaffolds or macrocyclic alpha helical modules, either alone, or within longer chain peptides or attached to other macrocyclic peptides or attached to non-peptidic structures, for the purpose of mimicking naturally occurring peptides or proteins, and as agonists or antagonists of the biological activity of naturally-occurring peptides or proteins or for the preparation of new materials.
• US8193310B2
  申请人：——

  公开号：US8193310B2

  公开（公告）日：2012-06-05
• US8629241B2
  申请人：——

  公开号：US8629241B2

  公开（公告）日：2014-01-14
• Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa
  作者：Sharon Jackson、W. DeGrado、A. Dwivedi、A. Parthasarathy、A. Higley、J. Krywko、A. Rockwell、J. Markwalder、G. Wells

  DOI：10.1021/ja00087a007

  日期：1994.4

  Although peptides adopt a large ensemble of conformations in aqueous solution, they are generally believed to bind to a receptor in a unique conformation. Thus, there is considerable interest in devising methods to restrict the conformational freedom of peptides. One such approach involves tying the amino and carboxy terminal ends of the peptide onto a semirigid template that will lock the intervening peptide backbone into a single conformer or a family of related conformers. This general strategy has been tested using the tripeptide sequence Arg-Gly-Asp (RGD), which binds with low affinity to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa or alpha(IIb)beta(3)) Mimics of RGD are of interest as antithrombotics because of their ability to inhibit the aggregation of platelets. Prior to this study, other workers (Samanen et al. J. Med. Chem. 1991, 34, 3114-3125) prepared a disulfide-containing cyclic pentapeptide that bound to GPIIb/IIIa with an affinity of approximately 0.1 mu M. NMR analysis of the solution conformation of this peptide suggested that replacing the disulfide-containing portion of the cycle with the amino acid m-(aminomethyl)benzoic acid would lead to a more rigid structure. Indeed, introduction of this template into a cyclic ROD-containing peptide resulted in compounds with high affinity for the receptor. Further, systematic inclusion of additional conformational constraints in the form of N-alpha- and C-alpha-alkyl groups led to a peptide with an affinity of approximately 100 pM for binding to the receptor. This peptide also showed good activity in the platelet aggregation assay at oral doses as low as 0.1 mg/kg.