His-[2-amino-iso-butyryl]-Glu-Gly-Thr-[(L)-α-methyl-(2,6-difluorophenyl)alanyl]-Thr-Ser-Asp-[2-amino-3-(2'-ethyl-4'-methoxy-biphenyl-4-yl)propanoyl]-[2-amino-3-(2'-methyl-biphenyl-4-yl)propanoyl]-NH2 | 516521-28-1

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: His-[2-amino-iso-butyryl]-Glu-Gly-Thr-[(L)-α-methyl-(2,6-difluorophenyl)alanyl]-Thr-Ser-Asp-[2-amino-3-(2'-ethyl-4'-methoxy-biphenyl-4-yl)propanoyl]-[2-amino-3-(2'-methyl-biphenyl-4-yl)propanoyl]-NH2
• 英文别名: His-Aib-Glu-Gly-Thr-[(L)-α-Me-(2,6-di-F)Phe]-Thr-Ser-Asp-(2'-Et,4'-OMe)BIP-(2'-Me)BIP-NH2；(4S)-4-[[2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-2-methylpropanoyl]amino]-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-[4-(2-methylphenyl)phenyl]-1-oxopropan-2-yl]amino]-3-[4-(2-ethyl-4-methoxyphenyl)phenyl]-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(2,6-difluorophenyl)-2-methyl-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-5-oxopentanoic acid
• CAS: 516521-28-1
• 化学式: C₇₆H₉₄F₂N₁₄O₁₉
• 分子量: 1545.66
• InChiKey: MYDGXJGACGCIOQ-PLQWGJBVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  111
• 可旋转键数：
  41
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  533
• 氢给体数：
  18
• 氢受体数：
  23

反应信息

• 作为产物：
  描述：

  (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl-amino)-3-(2'-ethyl-4'-methoxybi-phenyl-4-yl)propanoic acid 、 N-Fmoc-(s)-2,6-二氟-α-甲基苯基丙氨酸 、 Fmoc-甘氨酸 、 (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2'-methyl-[1,1'-biphenyl]-4-yl)propanoic acid 、 、 FMOC-O-叔丁基-L-丝氨酸 、 Fmoc-L-天冬氨酸 beta-叔丁酯 、 Fmoc-O-叔丁基-L-谷氨酸 、 Fmoc-O-叔丁基-L-苏氨酸 、 Fmoc-2-氨基异丁酸 在 N-甲基吗啉 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 以31%的产率得到His-[2-amino-iso-butyryl]-Glu-Gly-Thr-[(L)-α-methyl-(2,6-difluorophenyl)alanyl]-Thr-Ser-Asp-[2-amino-3-(2'-ethyl-4'-methoxy-biphenyl-4-yl)propanoyl]-[2-amino-3-(2'-methyl-biphenyl-4-yl)propanoyl]-NH2
  参考文献：
  名称：

  Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists

  摘要：

  Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonistis at nM concentrations in a cAMP assay. 2D NMR arid CD spectra revealed an N-terminal beta-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small Molecule agonists of the GLP-1 receptor to treat type 2 diabetes.

  DOI：

  10.1021/acs.jmedchem.5b00166

文献信息

• Eleven Amino Acid Glucagon-like Peptide-1 Receptor Agonists with Antidiabetic Activity
  作者：Claudio Mapelli、Sesha I. Natarajan、Jean-Philippe Meyer、Margarita M. Bastos、Michael S. Bernatowicz、Ving G. Lee、Jelka Pluscec、Douglas J. Riexinger、Ellen S. Sieber-McMaster、Keith L. Constantine、Constance A. Smith-Monroy、Rajasree Golla、Zhengping Ma、Daniel A. Longhi、Dan Shi、Li Xin、Joseph R. Taylor、Barry Koplowitz、Cecilia L. Chi、Ashish Khanna、Gordon W. Robinson、Ramakrishna Seethala、Ildiko A. Antal-Zimanyi、Robert H. Stoffel、Songping Han、Jean M. Whaley、Christine S. Huang、John Krupinski、William R. Ewing

  DOI：10.1021/jm900752a

  日期：2009.12.10

  Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a Mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.
• Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists
  作者：Huy N. Hoang、Kun Song、Timothy A. Hill、David R. Derksen、David J. Edmonds、W. Mei Kok、Chris Limberakis、Spiros Liras、Paula M. Loria、Vincent Mascitti、Alan M. Mathiowetz、Justin M. Mitchell、David W. Piotrowski、David A. Price、Robert V. Stanton、Jacky Y. Suen、Jane M. Withka、David A. Griffith、David P. Fairlie

  DOI：10.1021/acs.jmedchem.5b00166

  日期：2015.5.14

  Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonistis at nM concentrations in a cAMP assay. 2D NMR arid CD spectra revealed an N-terminal beta-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small Molecule agonists of the GLP-1 receptor to treat type 2 diabetes.