NDP-MSH | 75921-69-6

• 物质功能分类: 生物化工 - 多肽
• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: NDP-MSH
• 英文别名: Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2；NDP-αMSH；(Nle⁴, D-Phe⁷)-α-MSH；melanotan I；(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-5-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
• CAS: 75921-69-6
• 化学式: C₇₈H₁₁₁N₂₁O₁₉
• 分子量: 1646.87
• InChiKey: UAHFGYDRQSXQEB-LEBBXHLNSA-N

物化性质

• 密度：
  1.46±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -3.5
• 重原子数：
  118
• 可旋转键数：
  51
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  643
• 氢给体数：
  23
• 氢受体数：
  22

ADMET

代谢

阿法瑞林（afamelanotide）的代谢和代谢产物的详细信息很少。这种药物比其内源性对应物α-MSH对血清和蛋白水解酶的降解更具抵抗力，但由于其半衰期较短，可能发生相对较快的 hydrolysis。有人提出，阿法瑞林可能以与α-MSH相同的方式降解，但速率要慢得多，或者可能通过内吞作用或非特异性蛋白酶在细胞内降解。

Details regarding the metabolism and metabolites of afamelanotide are sparse. The drug is more resistant to degradation by serum and proteolytic enzymes than its endogenous counterpart, α-MSH, but presumably undergoes a relatively rapid hydrolysis given its short half-life.[L9086,L9134] It has been suggested that afamelanotide may be degraded in the same manner as α-MSH but at a much slower rate, or may instead be degraded intracellularly via endocytosis or non-specific proteases.[A187202]

来源:DrugBank

毒理性

• 毒性总结

关于afamelanotide过量的症状或治疗数据目前不可用。[L9086]

Data regarding symptoms or treatment of afamelanotide overdose are currently unavailable.[L9086]

来源:DrugBank

吸收、分配和排泄

• 吸收

阿法瑞林是一种通过皮下植入缓慢释放活性药物的制剂。大部分剂量在最初48小时内释放，到第五天时，释放量超过90%。给药后，阿法瑞林的血浆水平在接下来的几天内缓慢下降——在大多数临床试验受试者中，到第十天时，血浆水平已无法检测到。[L9086] 单次皮下植入给药后，中位达峰时间（T_max）为36小时，平均峰浓度（C_max）为3.7 ± 1.3 ng/mL，平均药时曲线下面积（AUC_0-∞）为138.9 ± 42.6 hr.ng/mL。[L9134]

Afamelanotide is administered as a subcutaneous implant that slowly elutes active drug. Most of the dose is released within the first 48 hours, with >90% released by day 5. Plasma levels of afamelanotide decrease slowly over the course of several days following administration - by day 10, plasma levels were undetectable in most clinical trial subjects.[L9086] Following administration of a single subcutaneous implant, the median T_max was 36 hours, the mean C_max was 3.7 ± 1.3 ng/mL, and the mean AUC_0-∞ was 138.9 ± 42.6 hr.ng/mL.[L9134]

来源:DrugBank

吸收、分配和排泄

• 消除途径

极少量未改变的阿法瑞林肽在给药后在尿液中回收，表明该药物被广泛代谢，很可能主要通过粪便或胆汁途径消除。

Minimal amounts of unchanged afamelanotide are recovered in the urine following administration, suggesting the drug is extensively metabolized and most likely eliminated primarily via fecal or biliary route.[A187202]

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药后，阿法瑞林酸的表观分布容积大约为0.54 L/kg。[A187202]

The apparent volume of distribution of afamelanotide following intravenous administration is approximately 0.54 L/kg.[A187202]

来源:DrugBank

吸收、分配和排泄

• 清除

关于afamelanotide的血浆清除数据有限。在皮下植入afamelanotide植入剂后，通常在第10天血浆中的药物水平检测不到。[L9086,A187205]

Data regarding plasma clearance of afamelanotide are limited. Plasma drug levels are typically undetectable at day 10 following subcutaneous administration of the afamelanotide implant.[L9086,A187205]

来源:DrugBank

安全信息

• WGK Germany：
  3

制备方法与用途

用途

美拉诺坦是一种多肽类化合物，可用作生化试剂。

用途

美拉诺坦 I 是 α-MSH 的合成类似物，它能够激动黑皮质素受体（MC1、MC3、MC4 和 MC5 受体的 Ki 值分别为 0.085、0.4、3.8 和 5.1 nM），适用于皮肤晒黑。

生物活性

美拉诺坦 I 是一种 α-黑色素细胞刺激素 (α-MSH) 类似物，主要用于促进皮肤晒黑。

参考质量标准

• 外观：白色粉末
• 纯度 (HPLC) ≥ 98.0%
• 醋酸根含量：5.0%～12.0%
• 水分含量 ≤ 8.0%
• 肽含量 ≥ 80.0%

反应信息

• 作为反应物：
  描述：

  NDP-MSH 、 [¹²⁵I]2,3,5,6-tetrafluorophenyl 4-fluoro-3-iodobenzoate 在 borate buffer 作用下， 以 乙腈 为溶剂， 反应 0.5h， 生成 [¹²⁵I][Nle4, D-Phe7, FIB-Lys11]α-MSH
  参考文献：
  名称：

  Development and Preliminary Evaluation of TFIB, a New Bimodal Prosthetic Group for Bioactive Molecule Labeling

  摘要：

  The new readily available prosthetic group, tetrafluorophenyl 4-fluoro-3-iodobenzoate (TFIB), designed for both molecular imaging and targeted radionuclide therapy purposes was radiolabeled either with fluorine or iodine radionuclides with excellent radiochemical yields and purities. These radiolabeled tags were conjugated to N,N-diethylethylenediamine to give melanin-targeting radiotracers [ (125) I]9 and [ (18) F]9, which were successfully evaluated by PET and gamma scintigraphic imaging in B16F0 pigmented melanoma-bearing C57BL/6J mice. Then, radiolabeled [ (125) I]/[ (18) F]TFIB was used to tag tumor-targeting peptides (i.e., PEG3[c(RGDyK)]2 and NDP-MSH targeting αvβ3 integrin and MC1R receptors, respectively) in mild conditions and with good radiochemical yields (47-83% d.c.) and purities (>99%). The resulting radiolabeled peptides were assessed both in vitro and by PET imaging in animal models.

  DOI：

  10.1021/ml500423v
• 作为产物：
  描述：

  Fmoc-甘氨酸 、 Fmoc-L-缬氨酸 、 Fmoc-L-脯氨酸 、 FMOC-O-叔丁基-L-丝氨酸 、 Fmoc-L-谷氨酸 、 Fmoc-O-叔丁基-L-酪氨酸 、 FMOC-赖氨酸 、 Fmoc-D-苯丙氨酸 、 N-Fmoc-N'-三苯甲基-L-组氨酸 、 芴甲氧羰酰基正亮氨酸 、 Fmoc-L-色氨酸(Boc)-OH 、 Fmoc-Pbf-L-精氨酸 在 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 N,N-二异丙基乙胺 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.83h， 生成 NDP-MSH
  参考文献：
  名称：

  具有典型氨基酸的MC1R选择性γ-MSH类似物的设计导致效价和色素沉着

  摘要：

  黑色素瘤是皮肤癌的致命形式。受黑色素皮质激素1受体（MC1R）调节的皮肤色素沉着是对黑色素瘤的有效保护。但是，内源性MC1R激动剂对MC1R缺乏选择性，因此会产生副作用。在先前的MC1R配体开发中使用非规范氨基酸引起了安全隐患。在这里，我们报告的第一个有效和选择性的hMC1R激动剂只有规范的氨基酸的发展。使用γ-MSH为模板，我们开发了一种肽，[亮氨酸3，亮氨酸7，苯丙氨酸8 ]-γ-MSH-NH 2（化合物5），其是用于hMC1R 16倍选择性（EC 50= 4.5 nM）与其他黑皮质素受体相比。构象研究揭示了该线性肽的受约束构象。分子对接表明黑皮质素1受体的疏水结合袋。体内色素沉着研究显示，效力高且持续时间短。[亮氨酸3，亮氨酸7，苯丙氨酸8 ]-γ-MSH-NH 2是理想的用于诱导短期的皮肤色素沉着，而不太阳黑素瘤预防。

  DOI：

  10.1021/acs.jmedchem.7b01295

文献信息

• Histidine-specific bioconjugation <i>via</i> visible-light-promoted thioacetal activation
  作者：Chuan Wan、Yuena Wang、Chenshan Lian、Qi Chang、Yuhao An、Jiean Chen、Jinming Sun、Zhanfeng Hou、Dongyan Yang、Xiaochun Guo、Feng Yin、Rui Wang、Zigang Li

  DOI：10.1039/d2sc02353a

  日期：——

  Histidine (His, H) undergoes various post-translational modifications (PTMs) and plays multiple roles in protein interactions and enzyme catalyzed reactions. However, compared with other amino acids such as Lys or Cys, His modification is much less explored. Herein we describe a novel visible-light-driven thioacetal activation reaction which enables facile modification on histidine residues. An efficient

  组氨酸 (His, H) 经历各种翻译后修饰 (PTM)，并在蛋白质相互作用和酶催化反应中发挥多种作用。然而，与 Lys 或 Cys 等其他氨基酸相比，His 修饰的探索要少得多。在这里，我们描述了一种新的可见光驱动的硫缩醛活化反应，该反应能够轻松修饰组氨酸残基。在生物相容性条件下对组氨酸咪唑 N3 的有效添加是通过亲电的锍中间体实现的。该方法允许对肽和蛋白质进行化学选择性修饰，具有良好的转化率和细胞裂解物的有效组氨酸蛋白质组分析。首次发现 78 种含组氨酸的蛋白质具有显着的富集，大多数在脑相关疾病中的金属积累中起作用。
• Compounds, compositions and methods for prevention and/or treatment of cancer
  申请人：THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

  公开号：US11369618B2

  公开（公告）日：2022-06-28

  The present invention includes compounds, compositions and methods that are useful for preventing or treating melanoma or any other cancer in a subject, such as a GPCR-expressing cancer. In certain embodiments, the compounds comprise estrogen (including estrogen derivatives or analogues), a selective GPER agonist and/or another G-protein coupled receptor (GPCR) agonist that increases cancer cell differentiation.

  本发明包括用于预防或治疗受试者的黑色素瘤或任何其他癌症（如表达 GPCR 的癌症）的化合物、组合物和方法。在某些实施方案中，化合物包括雌激素（包括雌激素衍生物或类似物）、选择性 GPER 激动剂和/或另一种能增加癌细胞分化的 G 蛋白偶联受体 (GPCR) 激动剂。
• COMPOUNDS, COMPOSITIONS AND METHODS FOR PREVENTION AND/OR TREATMENT OF CANCER
  申请人：THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

  公开号：US20200306261A1

  公开（公告）日：2020-10-01

  The present invention includes compounds, compositions and methods that are useful for preventing or treating melanoma or any other cancer in a subject, such as a GPCR-expressing cancer. In certain embodiments, the compounds comprise estrogen (including estrogen derivatives or analogues), a selective GPER agonist and/or another G-protein coupled receptor (GPCR) agonist that increases cancer cell differentiation.
• Development and Preliminary Evaluation of TFIB, a New Bimodal Prosthetic Group for Bioactive Molecule Labeling
  作者：Emilie M. F. Billaud、Aurélien Vidal、Amélie Vincenot、Sophie Besse、Bernadette Bouchon、Eric Debiton、Elisabeth Miot-Noirault、Imen Miladi、Latifa Rbah-Vidal、Philippe Auzeloux、Jean-Michel Chezal

  DOI：10.1021/ml500423v

  日期：2015.2.12

  The new readily available prosthetic group, tetrafluorophenyl 4-fluoro-3-iodobenzoate (TFIB), designed for both molecular imaging and targeted radionuclide therapy purposes was radiolabeled either with fluorine or iodine radionuclides with excellent radiochemical yields and purities. These radiolabeled tags were conjugated to N,N-diethylethylenediamine to give melanin-targeting radiotracers [ (125) I]9 and [ (18) F]9, which were successfully evaluated by PET and gamma scintigraphic imaging in B16F0 pigmented melanoma-bearing C57BL/6J mice. Then, radiolabeled [ (125) I]/[ (18) F]TFIB was used to tag tumor-targeting peptides (i.e., PEG3[c(RGDyK)]2 and NDP-MSH targeting αvβ3 integrin and MC1R receptors, respectively) in mild conditions and with good radiochemical yields (47-83% d.c.) and purities (>99%). The resulting radiolabeled peptides were assessed both in vitro and by PET imaging in animal models.
• Design of MC1R Selective γ-MSH Analogues with Canonical Amino Acids Leads to Potency and Pigmentation
  作者：Yang Zhou、Saghar Mowlazadeh Haghighi、Ioanna Zoi、Jonathon R. Sawyer、Victor J. Hruby、Minying Cai

  DOI：10.1021/acs.jmedchem.7b01295

  日期：2017.11.22

  the melanocortin 1 receptor (MC1R), is an effective protection against melanoma. However, the endogenous MC1R agonists lack selectivity for the MC1R and thus can have side effects. The use of noncanonical amino acids in previous MC1R ligand development raises safety concerns. Here we report the development of the first potent and selective hMC1R agonist with only canonical amino acids. Using γ-MSH as

  黑色素瘤是皮肤癌的致命形式。受黑色素皮质激素1受体（MC1R）调节的皮肤色素沉着是对黑色素瘤的有效保护。但是，内源性MC1R激动剂对MC1R缺乏选择性，因此会产生副作用。在先前的MC1R配体开发中使用非规范氨基酸引起了安全隐患。在这里，我们报告的第一个有效和选择性的hMC1R激动剂只有规范的氨基酸的发展。使用γ-MSH为模板，我们开发了一种肽，[亮氨酸3，亮氨酸7，苯丙氨酸8 ]-γ-MSH-NH 2（化合物5），其是用于hMC1R 16倍选择性（EC 50= 4.5 nM）与其他黑皮质素受体相比。构象研究揭示了该线性肽的受约束构象。分子对接表明黑皮质素1受体的疏水结合袋。体内色素沉着研究显示，效力高且持续时间短。[亮氨酸3，亮氨酸7，苯丙氨酸8 ]-γ-MSH-NH 2是理想的用于诱导短期的皮肤色素沉着，而不太阳黑素瘤预防。