Nα-t-BOC-N-α-methyl-Nω-tosyl-L-arginine

• 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: Nα-t-BOC-N-α-methyl-Nω-tosyl-L-arginine
• 英文别名: N-Boc-N-Me-N^g-p-tosyl-L-arginine；Boc-N-Me-Arg(Tos)-OH；(2S)-5-[[amino-[(4-methylphenyl)sulfonylamino]methylidene]amino]-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentanoic acid
• 化学式: C₁₉H₃₀N₄O₆S
• 分子量: 442.536
• InChiKey: OTYPUFUDTDVBRU-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  160
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Nα-t-BOC-N-α-methyl-Nω-tosyl-L-arginine 在 palladium on activated charcoal 氢气 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 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 8.08h， 生成 cyclohexyl 2-((5S,11S,14R)-14-isopropyl-2,12-dimethyl-4,7,10,13,16-pentaoxo-11-(3-(3-tosylguanidino)propyl)-3,6,9,12,15-pentaaza-1(1,3)-benzenacyclohexadecaphane-5-yl)acetate
  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
• 作为产物：
  描述：

  N'-对甲苯磺酰基-L-精氨酸 在 palladium on activated charcoal 盐酸 、 sodium hydroxide 、 甲酸 、 氢气 、 sodium cyanoborohydride 作用下， 以 甲醇 、 水 、 溶剂黄146 、 叔丁醇 为溶剂， 25.0 ℃ 、275.79 kPa 条件下， 反应 24.17h， 生成 Nα-t-BOC-N-α-methyl-Nω-tosyl-L-arginine
  参考文献：
  名称：

  Development of a small RGD peptide fibrinogen receptor antagonist with potent antiaggregatory activity in vitro

  摘要：

  The development of potent antithrombotic agents from the fibrinogen platelet receptor binding sequences Fg-alpha 572-575-Arg-Gly-Asp-Ser- and Fg-gamma 400-411-HHLGGAKQAGDV, believed to be a cryptic RGD-type sequence, is described. The tetrapeptide Ac-RGDS-NH2 itself is capable of inhibiting platelet aggregation in vitro at high concentrations, IC50 91.3 +/- 0.1-mu-M [in vitro antiaggregatory activity employing dog platelet rich plasma (PRP)/ADP], due to low platelet fibrinogen receptor affinity, K(i) 2.9 +/- 1.9-mu-M (purified, reconstituted human platelet GPIIb/IIIa), relative to fibrinogen, K(i) 38.0 +/- 6.0 nM. The peptide is also unstable to plasma, suffering total loss of in vitro activity upon incubation in PRP for 3 h (T1/2 90 min). Only modest improvements in potency were achieved with linear analogues of Ac-RGDS-NH2, while dramatic results were achieved with cyclic analogues, culminating in the cyclic disulfide Ac-cyclo-S,S-[Cys-(N-alpha-Me)Arg-Gly-Asp-Pen]-NH2 (SK&F 106760) with improved plasma stability (100% activity after 3 h), affinity (K(i) 58 +/- 20 nM purified human receptor), and potency (IC50 0.36 +/- 0.4-mu-M dog PRP/ADP). The affinity of this peptide is 2 orders of magnitude greater than that of Ac-RGDS-NH2. The affinity of the analogue is also comparable to fibrinogen. This peptide constitutes a first potent small peptide entry into the class of novel antithrombotic agents called fibrinogen receptor antagonists.

  DOI：

  10.1021/jm00114a022

文献信息

• In-Depth Study of Tripeptide-Based α-Ketoheterocycles as Inhibitors of Thrombin. Effective Utilization of the S₁‘ Subsite and Its Implications to Structure-Based Drug Design
  作者：Michael J. Costanzo、Harold R. Almond、Leonard R. Hecker、Mary R. Schott、Stephen C. Yabut、Han-Cheng Zhang、Patricia Andrade-Gordon、Thomas W. Corcoran、Edward C. Giardino、Jack A. Kauffman、Joan M. Lewis、Lawrence de Garavilla、Barbara J. Haertlein、Bruce E. Maryanoff

  DOI：10.1021/jm0303857

  日期：2005.3.1

  structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S(1)' region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate

  凝血酶抑制剂由于其抗凝和抗血栓形成作用而可能在医学上有用。我们基于d-Phe-Pro-Arg以及相关的凝血酶活性位点识别基序合成和评估了各种杂环活化的酮，作为候选抑制剂。基于肽的α-酮杂环通常通过亚氨酸酯或Weinreb酰胺途径制备（方案1和2），事实证明后者更为普遍。通常测定测试化合物对人α-凝血酶和牛胰蛋白酶的抑制作用。从基于结构的设计角度来看，杂环允许人们探索和调节凝血酶S1'亚位点内的相互作用。优选的α-酮杂环是富含pi的2取代的吡咯，在带有酮基的碳原子的附近至少有两个杂原子，优选的凝血酶抑制剂是2-酮基苯并噻唑3，其有效K（i）值为0.2 nM，约为1。选择性比胰蛋白酶高15倍。2-酮苯并噻唑13表现出极强的凝血酶抑制作用（K（i）= 0.000 65 nM;缓慢紧密结合）。几个α-酮杂环化合物的凝血酶K（i）值在0.1-400 nM范围内。在温和的碱性条件下，α-酮杂环的“ A
• The use of γ-turn mimetics to define peptide secondary structure
  作者：James F. Callahan、Kenneth A. Newlander、Joelle L. Burgess、Drake S. Eggleston、Andrew Nichols、Angela Wong、William F. Huffman

  DOI：10.1016/s0040-4020(01)90208-x

  日期：1993.3

  A novel γ-turn mimetic 2 has been prepared based on retro amide peptide design. Incorporation of this mimetic into linear peptide fibrinogen receptor antagonist 7 (GPIIb/IIIa receptor) affords the opportunity to test models of antagonist pharmacophore.

  基于逆酰胺肽设计，制备了新型的γ-转弯模拟物2。将此模拟物并入线性肽纤维蛋白原受体拮抗剂7（GPIIb / IIIa受体）中，提供了测试拮抗剂药效团模型的机会。
• Synthesis and some pharmacological properties of oxytocin and vasopressin analogs with sarcosine or N-methyl-L-alanine in position 7
  作者：Zbigniew Grzonka、Bernard Lammek、Franciszek Kasprzykowski、Diana Gazis、Irving L. Schwartz

  DOI：10.1021/jm00358a018

  日期：1983.4

  Eight analogues of oxytocin and arginine-vasopressin were synthesized, in which the proline residue in position 7 was replaced by either sarcosine or N-methylalanine; some of the pharmacological properties of these analogues were evaluated. In peptides containing a beta-mercaptopropionic acid residue in position 1, the additivity of the effects of deletion of the amino group in position 1 and of the

  合成了八种催产素和精氨酸加压素类似物，其中第7位的脯氨酸残基被肌氨酸或N-甲基丙氨酸取代；对这些类似物的某些药理特性进行了评估。在位置1含有β-巯基丙酸残基的肽中，确定了位置1的氨基缺失和位置7的上述取代对这些类似物的生物学特性的影响的可加性。发现所有类似物在抗利尿或子宫活性方面均有效，并且在作用上也具有选择性。从药理学性质的观点来看，在催产素第7位上的肌氨酸取代产生的类似物具有比N-甲基丙氨酸取代更高的催吐活性和射乳活性。
• Des-proline-N-methylarginine vasopressins
  申请人：SmithKline Beckman Corporation

  公开号：US04687758A1

  公开（公告）日：1987-08-18

  Peptides having vasopressin antagonist activity are prepared by a peptide synthesizer to insert a N-methylarginine at the 7-position of the structure. An example of this series of compounds is [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid)-2-(O-ethyl-D-tyrosine)-4-valine-7-desproline-8-N-methylarginine-9-de sglycine]-vasopressin.

  具有抗利尿激素活性的肽类通过肽合成器制备，将N-甲基精氨酸插入结构的7位。这一系列化合物的一个例子是[1-(β-巯基-β,β-环戊亚甲基丙酸)-2-(O-乙基-D-酪氨酸)-4-缬氨酸-7-去脯氨酸-8-N-甲基精氨酸-9-去甘氨酸]-利尿激素。
• Development of a small RGD peptide fibrinogen receptor antagonist with potent antiaggregatory activity in vitro
  作者：J. Samanen、F. Ali、T. Romoff、R. Calvo、E. Sorenson、J. Vasko、B. Storer、D. Berry、D. Bennett、M. Strohsacker、D. Powers、J. Stadel、A. Nichols

  DOI：10.1021/jm00114a022

  日期：1991.10.1

  The development of potent antithrombotic agents from the fibrinogen platelet receptor binding sequences Fg-alpha 572-575-Arg-Gly-Asp-Ser- and Fg-gamma 400-411-HHLGGAKQAGDV, believed to be a cryptic RGD-type sequence, is described. The tetrapeptide Ac-RGDS-NH2 itself is capable of inhibiting platelet aggregation in vitro at high concentrations, IC50 91.3 +/- 0.1-mu-M [in vitro antiaggregatory activity employing dog platelet rich plasma (PRP)/ADP], due to low platelet fibrinogen receptor affinity, K(i) 2.9 +/- 1.9-mu-M (purified, reconstituted human platelet GPIIb/IIIa), relative to fibrinogen, K(i) 38.0 +/- 6.0 nM. The peptide is also unstable to plasma, suffering total loss of in vitro activity upon incubation in PRP for 3 h (T1/2 90 min). Only modest improvements in potency were achieved with linear analogues of Ac-RGDS-NH2, while dramatic results were achieved with cyclic analogues, culminating in the cyclic disulfide Ac-cyclo-S,S-[Cys-(N-alpha-Me)Arg-Gly-Asp-Pen]-NH2 (SK&F 106760) with improved plasma stability (100% activity after 3 h), affinity (K(i) 58 +/- 20 nM purified human receptor), and potency (IC50 0.36 +/- 0.4-mu-M dog PRP/ADP). The affinity of this peptide is 2 orders of magnitude greater than that of Ac-RGDS-NH2. The affinity of the analogue is also comparable to fibrinogen. This peptide constitutes a first potent small peptide entry into the class of novel antithrombotic agents called fibrinogen receptor antagonists.