组氨瑞林 | 76712-82-8

• 物质功能分类: 生物化工 - 多肽
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 组氨瑞林
• 英文名称: Histrelin
• 英文别名: 6, Pro⁹-NH-C2H5>-GnRH；(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-3-(1-benzylimidazol-4-yl)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide
• CAS: 76712-82-8
• 化学式: C₆₆H₈₆N₁₈O₁₂
• 分子量: 1323.52
• InChiKey: HHXHVIJIIXKSOE-QILQGKCVSA-N

物化性质

• 比旋光度：
  D20 -33.9° (c = 1 in acetic acid)
• 密度：
  1.46±0.1 g/cm3(Predicted)
• 溶解度：
  酸水溶液（微溶）、DMSO（微溶）、甲醇（微溶）
• 蒸汽压力：
  0 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation = -33.9 deg at 20 °C/D ( c = 1 in acetic acid)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  96
• 可旋转键数：
  34
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  449
• 氢给体数：
  15
• 氢受体数：
  15

ADMET

代谢

一项使用人肝细胞的体外药物代谢研究中发现了一个单一的组氨酸代谢物，这是由于C端脱烷基作用产生的。由水解产生的肽片段也可能是一种代谢物。

An in vitro drug metabolism study using human hepatocytes identified a single histrelin metabolite resulting from C-terminal dealkylation. Peptide fragments resulting from hydrolysis are also likely metabolites.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

Histrelin在治疗期间与血清酶水平升高有关，其发生率与其他GnRH类似物相似。血清酶升高通常是轻微的、无症状的，即使不调整剂量或停药也能自行解决。ALT升高超过正常上限3倍的发生率不到1%。Histrelin曾与一例急性肝损伤有关，但报告不清楚这一事件是否与黄疸或症状有关，其他诊断仍然可能。因此，Histrelin引起的临床上明显的肝损伤可能发生，但极为罕见，病程通常是自限性的。目前尚未有急性肝衰竭、慢性肝炎或胆管消失综合征与Histrelin或其他GnRH类似物治疗相关的报告。

Histrelin has been associated with serum enzyme elevations during therapy in rates similar to those of other GnRH analogues. The serum enzyme elevations are generally mild, asymptomatic and resolve even without dose adjustment or drug discontinuation. ALT elevations above 3 times the upper limit of normal occur in less than 1% of recipients. Histrelin has been linked to a single case of acute liver injury, but it was unclear from the report whether the episode was associated with jaundice or symptoms and other diagnoses remained possible. Thus, clinically apparent liver injury from histrelin may occur, but it is extremely rare and usually self-limited in course. There have been no episodes of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with histrelin or other GnRH analogue therapy.

来源:LiverTox

毒理性

• 解毒与急救

保持呼吸道通畅，必要时辅助通气。如果出现昏迷、抽搐、低血压和心律失常，则进行治疗。对于恶心和呕吐，使用甲氧氯普胺治疗，对于胃肠炎引起的液体丢失，使用静脉晶体液治疗。对于骨髓抑制，应在经验丰富的血液学家或肿瘤学家的帮助下进行治疗。外渗：立即停止输液，并通过注射器的负压尽可能多地抽回液体。... /对于/ 清除污染，如果条件适当，口服活性炭。在小到中等量的摄入后，如果可以迅速给予活性炭，则不需要进行洗胃。由于这些药物的快速细胞内结合，透析和其他体外去除程序通常无效。 /抗肿瘤药物/

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. ... /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

立即急救：确保已经进行了充分去污。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、气囊面罩装置或口袋面罩，按训练进行操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者向前倾或将其置于左侧（如果可能，头部向下），以保持呼吸道畅通并防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。/毒物A和B/

Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道（如需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的呕吐反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干性无菌敷料覆盖皮肤烧伤……。/毒物A和B/

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β受体激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W/SRP：“保持开放”，最小流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

醋酸组抑制素口服给药时不活跃。

Histrelin acetate is not active when given orally.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在患有晚期前列腺癌的患者中，植入醋酸组抑制剂的植入物后，组抑制素的血清浓度峰值在中位数12小时出现；该药物以每天50-60微克的速率持续释放，持续12个月。

Following subcutaneous insertion of a histrelin acetate implant in patients with advanced prostate cancer, peak serum concentrations of histrelin occurred at a median of 12 hours; the drug is delivered continuously at a rate of 50-60 ug daily over 12 months.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在17名晚期前列腺癌患者中，皮下植入一个Vantas（醋酸己烯雌酚植入剂）50毫克植入剂后，血药浓度峰值达到1.10 +/- 0.375纳克/毫升（平均值 +/- 标准差），中位时间为12小时。

Following subcutaneous insertion of one Vantas (histrelin implant) 50 mg implant in advanced prostate cancer patients (n = 17), peak serum concentrations of 1.10 +/- 0.375 ng/mL (mean +/- SD) occurred at a median of 12 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

从41个植入物中检测残余药物含量的平均皮下释药速率为56.7 +/- 7.71微克/天，在整个52周的给药期间。

The average rate of subcutaneous drug release from 41 implants assayed for residual drug content was 56.7 +/- 7.71 ug/day over the 52 week dosing period.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S22,S36/37/39,S45,S53
• 危险类别码：
  R60
• WGK Germany：
  3
• RTECS号：
  OK6370800
• 海关编码：
  2937190090
• 储存条件：
  室温且干燥

制备方法与用途

化学性质：[ \alpha ]D₂₀ - 33.9°（C=1，乙酸）。

用途：用于治疗青春期提前发育。

反应信息

• 作为反应物：
  描述：

  组氨瑞林 在 水 作用下， 反应 432.0h， 生成 (2S)-2-[[(2S)-3-(1H-imidazol-5-yl)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid 、 His-Trp-Ser-Tyr-(D-N^im-bzl-His)-Leu-Arg-Pro-NHEt 、 cyclo(-His-Trp) 、 Ser-Tyr-(D-N^im-bzl-His)-Leu-Arg-Pro-NHEt 、 L-焦谷氨酸
  参考文献：
  名称：

  促性腺激素释放激素（LH / RH）激动剂Histrelin的溶液降解产物的表征

  摘要：

  在pH 5.4和87摄氏度的水溶液中测定了组蛋白的降解产物（1，小于Glu-His-Trp-Ser-Tyr-（D-Nim-bzl-His）-Leu-Arg-Pro-NHEt）在18天的时间内（降级47％）。这些降解产物（2-5）是由于少于Glu-His和Trp-Ser肽键的裂解，His-Trp二酮哌嗪的形成以及丝氨酸和组氨酸残基的消旋作用所致。

  DOI：

  10.1002/jps.2600800316

文献信息

• Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
  申请人：Xu Feng

  公开号：US20100120727A1

  公开（公告）日：2010-05-13

  In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.

  在一个方面，本发明提供了一种氟硝西汀类似物与抗炎药物的共价结合物的组合物。在另一个方面，本发明提供了一种氟硝西汀前药的组合物。在另一个方面，本发明提供了一种氟硝西汀或其衍生物水杨酸盐的组合物。在另一个方面，本发明提供了使用氟硝西汀类似物或氟硝西汀前药的共轭物或盐来治疗或预防癌症的方法。
• BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20190300521A1

  公开（公告）日：2019-10-03

  The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为SMARCA2或BRM（靶蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合Von Hippel-Lindau E3泛素连接酶的配体，另一端结合靶蛋白的双功能化合物，使得靶蛋白与泛素连接酶靠近以实现靶蛋白的降解（和抑制）。本公开展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由靶蛋白聚集或积累导致的疾病或紊乱。
• [EN] ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE<br/>[FR] MODULATEURS DE PROTÉOLYSE À BASE D'ALANINE ET PROCÉDÉS D'UTILISATION ASSOCIÉS
  申请人：ARVINAS INC

  公开号：WO2017011590A1

  公开（公告）日：2017-01-19

  The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

  描述涉及抑制凋亡蛋白（TAPs）结合化合物，包括包含相同的A功能化合物，这些化合物作为靶向泛素化的调节剂发挥作用，特别是根据本发明的双功能化合物抑制各种多肽和其他蛋白质的化合物。具体而言，描述提供了一端含有结合到IAP E3泛素连接酶的配体，另一端含有结合到靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。可以合成化合物，表现出与几乎任何类型的靶向多肽的降解/抑制一致的广泛药理活性。
• [EN] COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION CIBLÉE DE PROTÉINES CONTENANT UN BROMODOMAINE
  申请人：ARVINAS INC

  公开号：WO2017030814A1

  公开（公告）日：2017-02-23

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是根据本发明抑制各种多肽和其他蛋白质的化合物。具体而言，本发明涉及一端含有结合泛素连接酶的VHL配体，另一端含有结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。根据本发明的化合物表现出与靶向多肽的降解/抑制一致的广泛的药理活性。
• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES
  申请人：Arvinas, Inc.

  公开号：US20190151295A1

  公开（公告）日：2019-05-23

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为白细胞介素-1受体相关激酶4（IRAK-4；目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合E3泛素连接酶的Von Hppel-Lindau、cereblon配体的双功能化合物，另一端结合目标蛋白的部分，使得目标蛋白靠近泛素连接酶以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。