N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Trp-Pro-D-Arg-NH2 | 138207-84-8

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Trp-Pro-D-Arg-NH2
• 英文别名: N-[(5R)-6-[(2S)-1-[(2S)-1-[(2S)-2-[N-[(2R)-5-carbamimidamido-1-hydroxy-1-iminopentan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidin-1-yl]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-5-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-3-(4-chlorophenyl)-1-hydroxy-2-[[(2R)-1-hydroxy-2-(1-hydroxyethylideneamino)-3-naphthalen-2-ylpropylidene]amino]propylidene]amino]-1-hydroxy-3-pyridin-3-ylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-6-[[hydroxy(pyridin-2-yl)methylidene]amino]hexylidene]amino]-6-hydroxyhexyl]pyridine-2-carboximidic acid
• CAS: 138207-84-8
• 化学式: C₈₇H₁₀₇ClN₂₀O₁₄
• 分子量: 1692.39
• InChiKey: LLRPOSCCSGZTGQ-RAKUWOBTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  11.8
• 重原子数：
  122
• 可旋转键数：
  47
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  560
• 氢给体数：
  18
• 氢受体数：
  30

反应信息

• 作为产物：
  描述：

  N-Ac-D-Nal-D-Cpa-D-Pal-Ser(Bzl)-Lys(Pic)-D-Lys(Pic)-Leu-Trp-Pro-D-Arg(Tos)-NH2 在 氢氟酸 、 苯甲醚 作用下， 反应 1.0h， 以45 mg的产率得到N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Trp-Pro-D-Arg-NH2
  参考文献：
  名称：

  Decreased histamine release by luteinizing-hormone-releasing-hormone antagonists obtained upon translocation of the cationic amino acid from position 8 to position 7

  摘要：

  We report analogues of N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Ilys-Pro-D-Ala-NH2, the parent antagonist (PA), which is a potent antagonist of LHRH. To simplify future radioactive labeling we prepared N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Arg-Pro-D-Ala-NH2 (4), [Arg8]PA, which had good activity in the antiovulatory assay (AOA). Other analogues were designed at first by substituting with Arg at positions 5, 6, 7, 9, and 10, and Trp or Leu at position 8. Subsequent analogues were prepared in attempts to improve the AOA of the initial ones. Substitutions with Arg9 or Arg10 led to analogues 1-3 with no AOA activity at 5-mu-g/rat. However, substitution with Arg7 gave 9, [Arg7,Leu8]PA, with significant activity in the AOA at 5-mu-g/rat and borderline activity at 2.5-mu-g/rat, and substitution with Ilys7 gave 13, [Ilys7,Leu8]PA, with borderline activity at 2-mu-g/rat, both analogues showing much weaker activity than PA in the histamine release assay (HRA) and therefore being potentially safer. Substitutions with D-Arg6 or Arg5 led to analogues with either good AO activity at 5-mu-g/rat (analogue 7) or with borderline activity at 5-mu-g/rat (analogue 8), although both were more potent than 6 in the HRA. Combinations of Ilys or Arg at positions 7 and 8 led to 10 and 11, both of which were tested at 2-mu-g/rat and found to have either good AO activity (analogue 10) or borderline activity (analogue 11) but unsuitably potent in HR. Substitutions using Ilys7 and neutral amino acids at position 8 led to 14-17 which were inactive in the AOA. Of great significance is the substitution with Arg7 yielding analogue 9, which was much safer in the HRA than analogue 4, [Arg8]PA. Analogues 9 and 13, featuring substitutions with the Arg7-Leu8 or Ilys7-Leu8 sequences were even safer than PA or 6 in the HRA. Analogue 12, [D-Trp3,Tyr5,D-Arg6,Arg7,Leu8]PA, featuring the Arg7-Leu8 sequence, had much lower potency in the HRA than [D-Trp3,Tyr5,D-Arg6,Leu7,Arg8]PA, which has the normal Leu7-Arg8 sequence. Ilys7 together with neutral amino acids at position 8 led to analogues 14-17 which were also very weak (safer) in the HRA, with the smaller amino acids Ala8 and Abu8 being the weakest of all analogues prepared. The translocation of the strongly basic amino acid, as developed for analogues 9 and 13, may be an attractive new approach to the design of safer AO analogues which low histamine release.

  DOI：

  10.1021/jm00082a004