N-甲酰基-L-组氨酸 | 15191-21-6

• 物质功能分类: 生物化工 - 氨基酸及其衍生物 - 组氨酸类衍生物
• 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
• 中文名称: N-甲酰基-L-组氨酸
• 中文别名: N-甲酰-L-组氨酸
• 英文名称: N-formyl histidine
• 英文别名: N^α-Formyl-L-histidin；N-formyl-L-histidine；N^α-formyl-histidine；(2S)-2-formamido-3-(1H-imidazol-3-ium-5-yl)propanoate
• CAS: 15191-21-6
• 化学式: C₇H₉N₃O₃
• 分子量: 183.167
• InChiKey: WFQVSLVQIFFQQN-LURJTMIESA-N

物化性质

• 熔点：
  202.0 to 206.0 °C
• 沸点：
  644.5±50.0 °C(Predicted)
• 密度：
  1.431±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  13
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  95.1
• 氢给体数：
  3
• 氢受体数：
  4

安全信息

• 海关编码：
  2933290090
• 安全说明：
  S22,S24/25

反应信息

• 作为反应物：
  描述：

  (2R,3S,4S)-3-hexyl-4-(2-hydroxy-pentadecyl)-oxetan-2-one 、 N-甲酰基-L-组氨酸 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 以17%的产率得到(S)-2-formylamino-3-(3H-imidazol-4-yl)-propionic acid 1-((2S,3S,4S)-3-hexyl-4-oxo-oxetan-2-ylmethyl)-tetradecyl ester
  参考文献：
  名称：

  Synthesis of Novel β-Lactone Inhibitors of Fatty Acid Synthase

  摘要：

  Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report oil the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and arnino ester substitutions were altered and tile resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display all increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings Support the idea that all orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.

  DOI：

  10.1021/jm800321h
• 作为产物：
  描述：

  甲酸 、 L-组氨酸 在 碳酸二甲酯 作用下， 以99%的产率得到N-甲酰基-L-组氨酸
  参考文献：
  名称：

  氨基酸合成的新方法：与碳酸二甲酯进行酸辅助反应，生成高效的 O-甲基化、N,O-甲基化和 N-甲酰化衍生物

  摘要：

  开发了一种使用碳酸二甲酯 (DMC) 和酸系统修饰氨基酸的新颖且有效的方法。使用这种简单的酸辅助方法，已成功实现各种氨基酸的N-甲基化、N , O-二甲基化和N-甲酰化（>99% 转化率和 >99% 产率），并且使用 NMR 充分表征了修饰的氨基酸光谱学。该方法具有多种优点，包括使用可持续且经济高效的试剂、高选择性、高效、生态友好、广泛适用于具有不同侧链功能的一系列氨基酸，并且确信存在无外消旋化和差向异构化风险。这项研究为氨基酸修饰提供了一种新的、可持续的、实用的方法，在药物发现和化学生物学方面具有潜在的应用。

  DOI：

  10.1039/d3gc03455k

文献信息

• DERIVATIVES OF GLP-1 LIKE PEPTIDES, AND USES THEREOF
  申请人：Novo Nordisk A/S

  公开号：US20150011462A1

  公开（公告）日：2015-01-08

  The invention relates to derivatives of GLP-1 like peptides which are C-terminally extended analogues of native GLP-1. The derivatives comprise two side chains, one at a position corresponding to position 42, and one at a position corresponding to position 18, 23, 27, 31, 36, or 38, wherein both positions are when compared to GLP-1(7-37). The side chains comprise a C19, C20, or C22 diacid protracting moiety and optionally a linker. The invention also relates to intermediate products in the form of novel GLP-1 analogues incorporated in the derivatives of the invention, as well as pharmaceutical compositions and medical uses of the derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

  该发明涉及GLP-1样肽的衍生物，这些衍生物是原生GLP-1的C-末端延长类似物。这些衍生物包括两个侧链，一个位于相对于位置42的位置，另一个位于相对于位置18、23、27、31、36或38的位置，其中这两个位置均与GLP-1(7-37)进行比较。这些侧链包括C19、C20或C22二酸延伸基团，可选地包括一个连接物。该发明还涉及作为新GLP-1类似物的中间产物，这些类似物被合并在该发明的衍生物中，以及这些衍生物的药物组合物和医疗用途。这些衍生物具有非常长的半衰期，同时保持了令人满意的效力，这使它们有可能适合每月一次的给药。
• GLP-1 Derivatives and Uses Thereof
  申请人：Novo Nordisk A/S

  公开号：US20160143998A1

  公开（公告）日：2016-05-26

  The invention relates to a derivative of a GLP-1 analogue, optionally C-terminally extended, which derivative comprises a first and a second protracting moiety in the form of a C20 or C22 diacid radical, a bis-amino branched linker, and a first and a second further linker each comprising an OEG-like linker element; wherein these elements are interconnected via amide bonds and attached to a Lys residue of the GLP-1 analogue. The invention also relates to intermediate products in the form of novel GLP-1 analogues incorporated in the derivatives of the invention, as well pharmaceutical compositions and medical uses of the derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

  该发明涉及一种GLP-1类似物的衍生物，可选择地在C-末端延长，该衍生物包括形式为C20或C22二酸基团的第一和第二延长基团，一种双氨基支链连接剂，以及包括类似OEG的连接元素的第一和第二进一步连接剂；其中这些元素通过酰胺键相互连接，并连接到GLP-1类似物的一个赖氨酸残基上。该发明还涉及中间产物，即新型GLP-1类似物，这些类似物包含在该发明的衍生物中，以及该衍生物的药物组合物和医药用途。这些衍生物具有非常长的半衰期，同时保持了令人满意的效力，这使它们有可能适合每月一次的给药。
• GLP-1 Derivatives, and Uses Thereof
  申请人：NOVO NORDISK A/S

  公开号：US20160200791A1

  公开（公告）日：2016-07-14

  The present invention relates to tri-acylated GLP-1 derivatives, acylated at positions corresponding to positions (18, 22, 30), (18, 26, 37), (18, 27, 37), (26, 30, 37), or (27, 30, 37) of the native human glucagon-like peptide 1 (GLP-1 (7-37) (SEQ ID NO: 1); or pharmaceutically acceptable salts, amides, or esters thereof. The acylated side chains comprise a protracting moiety selected from Chem. 1: HOOC—(CH 2 ) 16 —CO—*, Chem. 1a: HOOC—(CH 2 ) 18 —CO—*, and Chem. 2: HO 3 S—(CH 2 ) 15 —CO—*, and the protracting moieties are connected, via a linker, to a Lys residue of the GLP-1 peptide. The GLP-1 peptide has a maximum of seven amino acid changes as compared to GLP-1 (7-37) (SEQ ID NO: 1). The invention also relates to intermediate products in the form of novel GLP-1 analogues, as well as to pharmaceutical compositions and uses of the derivatives and analogues, in particular for the treatment of type 2 diabetes. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

  本发明涉及三酰化GLP-1衍生物，酰化位置与人源胰高血糖素样肽1（GLP-1（7-37）（序列号：1））的位置（18、22、30）、（18、26、37）、（18、27、37）、（26、30、37）或（27、30、37）相对应，并且其药学上可接受的盐、酰胺或酯。酰化侧链包括从化学1: HOOC—(CH2)16—CO—*、化学1a: HOOC—(CH2)18—CO—*和化学2: HO3S—(CH2)15—CO—*中选择的延长基团，并且通过连接器连接到GLP-1肽的一个赖氨酸残基。与GLP-1（7-37）（序列号：1）相比，GLP-1肽最多有七个氨基酸变化。该发明还涉及作为新GLP-1类似物的中间产物，以及衍生物和类似物的药物组合物和用途，特别是用于治疗2型糖尿病。这些衍生物具有非常长的半衰期，同时保持了令人满意的效力，这使它们有可能适合每月一次的给药。
• [EN] GLP-1 DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE GLP-1 ET LEURS UTILISATIONS
  申请人：NOVO NORDISK AS

  公开号：WO2016083499A1

  公开（公告）日：2016-06-02

  The invention relates to a derivative of a GLP-1 analogue of a general Formula I, which derivative comprises a side chain attached to a Lys residue at position 34, 35, 36, 37, or 38 of the GLP-1 analogue, which side chain comprises a Branched linker, a 1st and a 2nd Protractor selected from C18 diacid, C20 diacid, and sulfonic acid C16, and at least one Linker element-1 incorporating ethylene glycol units. Linker element-1 may be incorporated in an optional Pre-linker, and/or in a 1st or 2nd Post-linker. The invention also relates to novel GLP-1 analogues, novel side chain intermediate products and their manufacture and use to prepare derivatives of biologically active peptides and proteins, as well as pharmaceutical compositions and medical uses of the analogues and derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

  这项发明涉及通用公式I的GLP-1类似物的衍生物，该衍生物包括连接到GLP-1类似物的第34、35、36、37或38位的Lys残基的侧链，该侧链包括一个分支连接物、从C18二酸、C20二酸和磺酸C16中选择的第一和第二伸缩剂，以及至少一个包含乙二醇单元的连接元素-1。连接元素-1可以被合并到一个可选的前连接物中，和/或第一或第二后连接物中。该发明还涉及新型GLP-1类似物、新型侧链中间体产品及其制备和用于制备生物活性肽和蛋白质衍生物的用途，以及类似物和衍生物的药物组合物和医疗用途。这些衍生物具有非常长的半衰期，同时保持令人满意的效力，因此它们有潜在适用于每月一次的给药。
• Double-acylated GLP-1 derivatives
  申请人：Novo Nordisk A/S

  公开号：US10000542B2

  公开（公告）日：2018-06-19

  The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue and a second K residue, at positions corresponding to position 26, and 37, respectively, of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of eight amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1: HOOC—(CH2)x—CO—*, and Chem. 2: HOOC—C6H4—O—(CH2)y—CO—*, in which x is an integer in the range of 8-16, and y is an integer in the range of 6-13; and the linker comprises Chem. 3: *—NH—(CH2)q—CH[(CH2)w—NR1R2]—CO—*, which is connected at its CO—* end to the epsilon amino group of the first or the second K residue of the GLP-1 analogue, and wherein q is an integer in the range of 0-5, R1 and R2 independently represent *—H or *—CH3, and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptide and linker intermediates. The derivatives are potent, stable, protracted, and suitable for oral administration.

  本发明涉及一种GLP-1类似物的衍生物，该类似物包括第一个K残基和第二个K残基，分别位于与GLP-1（7-37）（SEQ ID NO：1）的位置26和37相对应的位置上，并且与GLP-1（7-37）相比最多有八个氨基酸变化；该衍生物包括通过连接剂连接到所述第一个和第二个K残基上的两个延长基团，其中所述延长基团选自Chem.1：HOOC-（CH2）x-CO-*和Chem.2：HOOC-C6H4-O-（CH2）y-CO-*，其中x为8-16的整数范围内的整数，y为6-13的整数范围内的整数；连接剂包括Chem.3：* -NH-（CH2）q-CH [（CH2）w-NR1R2] -CO- *，它在其CO- *端连接到GLP-1类似物的第一个或第二个K残基的epsilon氨基基团上，其中q为0-5的整数范围内的整数，R1和R2独立地表示* -H或* -CH3，w为0-5的整数范围内的整数；或其药学上可接受的盐，酰胺或酯。本发明还涉及其在治疗和/或预防所有形式的糖尿病和相关疾病中的药物应用，以及相应的新型肽和连接剂中间体。这些衍生物具有高效、稳定、持久和适合口服给药的特点。

表征谱图