protease-activated receptor-1 agonist peptide

• 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: protease-activated receptor-1 agonist peptide
• 英文别名: Ser-Phe-Leu-Leu-Arg-NH2；SFLLR-NH2；PAR-1 agonist peptide；SFLLR-NH₂；TP5-NH2；H-Ser-phe-leu-leu-arg-NH2；(2S)-N-[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-2-[[(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanamide
• 化学式: C₃₀H₅₁N₉O₆
• 分子量: 633.792
• InChiKey: CDBPTZOOUNAWQA-LSBAASHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  45
• 可旋转键数：
  20
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  270
• 氢给体数：
  9
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  BOC-L-亮氨酸 、 BOC-L-苯丙氨酸 、 N-叔丁氧羰基-N'-甲苯磺酰基-L-精氨酸 、 N-BOC-O-苄基-L-丝氨酸 生成 protease-activated receptor-1 agonist peptide
  参考文献：
  名称：

  Development of a Potent Thrombin Receptor Ligand

  摘要：

  The N-terminal thrombin receptor peptide H-Ser-Phe-Leu-Leu-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-Glu-Pro-Phe-OH (1) fully activates the thrombin receptor with an EC(50) Of 10 mu M Structural features in the tetradecapeptide which are responsible for receptor activation have been elucidated. Agonist potency has been enhanced 1000-fold with the design of the shortened peptide H-Ala-Phe(p-F)-Arg-Cha-HArg-Tyr-NH2 (56). This analog exhibits an EC(50) of 0.01 mu M and is the most potent agonist for receptor activation reported to date. The monoiodinated derivative H-Ala-Phe(p-F)-Arg-Cha-HArg-Tyr(3-I)-NH2 (59) exhibits an EC(50) of 0.03 mu M, a level sufficient for development of a radioligand.

  DOI：

  10.1021/jm00020a029

文献信息

• Development of Potent Thrombin Receptor Antagonist Peptides
  作者：Michael S. Bernatowicz、Clifford E. Klimas、Karen S. Hartl、Marianne Peluso、Nick J. Allegretto、Steven M. Seiler

  DOI：10.1021/jm960455s

  日期：1996.1.1

  A peptide-based structure-activity study is reported leading to the discovery of novel potent thrombin receptor antagonists. Systematic substitution of nonproteogenic amino acids for the second and third residues of the human thrombin receptor ''tethered ligand'' sequence (SFLLR) led to a series of agonists with enhanced potency. The most potent pentapeptide agonist identified was Ser-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2, 9 (EC(50) similar to 0.04 mu M for stimulation of human platelet aggregation, similar to 10-fold more potent than the natural pentapeptide). Systematic substitution of the NH2-terminal Ser in 9 with neutral hydrophobic NH2-acyl groups led to partial agonists and eventually antagonists with unprecedented potency (greater than 1000-fold increase over the previously reported antagonist 3-mercaptopropionyl-Phe-Cha-Cha-Arg-Lys-Pro-Asn-Asp-Lys-NH2). In the series of NH2-acyl tetrapeptide antagonists, N-trans-cinnamoyl-p-fluoroPhe-p-guanidino-Phe-Leu-Arg-NH2, 41 (BMS-197525), was identified as the tightest binding (IC50 similar to 8 nM) and most potent with an IC50 similar to 0.20 mu M for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. Systematic single substitutions in 41 indicated that, in addition to the NH2-terminal acyl group, the side chains at the second and third positions were also responsible for important and specific receptor interactions. The p-fluoroPhe and p-guanidinoPhe residues in the second and third positions of 41 were observed to be optimal in both the agonist and antagonist series. In the case of antagonists, however, an appropriately positioned positively charged group (i.e., protonated base) at the third residue was required. In contrast, such a substitution was not required for potent agonist activity. An even more potent antagonist resulted when 41 was extended at the C-terminus by a single Arg residue giving rise to analog 90 (BMS-200261) which had an IC50 similar to 20 nM for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. When the C-terminal Arg of 90 was replaced by an Orn-(N-delta-propionyl) residue, the resulting antagonist 91 (BMS-200661) was suitable for use in radioligand binding assays (K-d = 10-30 nM). Antagonist activity observed for selected compounds was verified through secondary assays in that these analogs prevented SFLLRNP-NH2-stimulated GTPase activity in platelet membranes and Ca2+ mobilization in cultured human smooth muscle cells and mouse fibroblasts. Furthermore, this inhibition occurred at concentrations that had no effect on thrombin catalytic activity indicating a specific activity attributable to receptor binding and not enzyme inhibition.
• Development of a Potent Thrombin Receptor Ligand
  作者：Dong-Mei Feng、Daniel F. Veber、Thomas M. Connolly、Cindra Condra、Mei-Jy Tang、Ruth F. Nutt

  DOI：10.1021/jm00020a029

  日期：1995.9

  The N-terminal thrombin receptor peptide H-Ser-Phe-Leu-Leu-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-Glu-Pro-Phe-OH (1) fully activates the thrombin receptor with an EC(50) Of 10 mu M Structural features in the tetradecapeptide which are responsible for receptor activation have been elucidated. Agonist potency has been enhanced 1000-fold with the design of the shortened peptide H-Ala-Phe(p-F)-Arg-Cha-HArg-Tyr-NH2 (56). This analog exhibits an EC(50) of 0.01 mu M and is the most potent agonist for receptor activation reported to date. The monoiodinated derivative H-Ala-Phe(p-F)-Arg-Cha-HArg-Tyr(3-I)-NH2 (59) exhibits an EC(50) of 0.03 mu M, a level sufficient for development of a radioligand.