硼替佐米 | 179324-69-7

• 物质功能分类: 原料药 - 抗肿瘤药 - 其它抗肿瘤药
• 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: 硼替佐米
• 中文别名: 硼替佐米杂质；N-(2-吡嗪羰基)-L-苯丙氨酸-L-亮氨酸硼酸；保特佐米；[(1R)-3-甲基-1-[[(2S)-1-氧-3-苯基-2-[(吡嗪甲酰)氨基]丙基]氨基]丁基]-硼酸
• 英文名称: velcade
• 英文别名: Bortezomib；Btz；PS 341；[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid；[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid；[(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid；[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2-ylformamido)propanamido]butyl]boronic acid；((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)boronic acid；MG-341；BZM；BOR
• CAS: 179324-69-7
• 化学式: C₁₉H₂₅BN₄O₄
• 分子量: 384.243
• InChiKey: GXJABQQUPOEUTA-RDJZCZTQSA-N

物化性质

• 熔点：
  122-124°C
• 密度：
  1.214
• 溶解度：
  易溶于氯仿、二甲基亚砜、乙醇和甲醇。
• 物理描述：
  Solid
• 颜色/状态：
  Powder
• 蒸汽压力：
  5.1X10-20 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Hygroscopic and moisture sensitive

计算性质

• 辛醇/水分配系数(LogP)：
  0.36
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  124
• 氢给体数：
  4
• 氢受体数：
  6

ADMET

代谢

硼替佐米主要通过CYP3A4、CYP2C19和CYP1A2代谢。CYP2D6和CYP2C9也参与了药物代谢，但程度较小。氧化脱硼，涉及从母化合物中去除硼酸，是主要的代谢途径。硼替佐米的代谢物在药理上是无效的，在人类和动物研究中已经鉴定出超过30种代谢物。

Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent. Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies.

来源:DrugBank

代谢

体外研究使用人肝微粒体和人cDNA表达的细胞色素P450同工酶表明，硼替佐米主要通过细胞色素P450酶3A4、2C19和1A2进行氧化代谢。CYP 2D6和2C9酶对硼替佐米的代谢作用较小。主要的代谢途径是脱硼，形成2种脱硼代谢物，随后这些代谢物经过羟基化形成多种代谢物。脱硼的硼替佐米代谢物作为26S蛋白酶体抑制剂是无活性的。来自8名患者在给药后10分钟和30分钟的混合血浆数据显示，与母药相比，代谢物的血浆水平较低。

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

硼替佐米及其主要脱硼代谢物M1和M2以及它们的脱烷基代谢物M3和M4在人肝微粒体中对主要P450同种物1A2、2C9、2C19、2D6和3A4/5的P450抑制潜力进行了评估。硼替佐米、M1和M2被发现是CYP2C19的轻微抑制剂（IC50分别约为18.0、10.0和13.2微米），M1也是CYP2C9的轻微抑制剂（IC50约为11.5微米）。然而，硼替佐米、M1、M2、M3和M4并未抑制其他P450（IC50值>30微米）。硼替佐米或其主要代谢物对CYP3A4/5也没有时间依赖性抑制。

... The P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2 and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. Bortezomib, M1, and M2 were found to be mild inhibitors of CYP2C19 (IC(50) approximately 18.0, 10.0, and 13.2 microM, respectively), and M1 was also a mild inhibitor of CYP2C9 (IC(50) approximately 11.5 microM). However, bortezomib, M1, M2, M3, and M4 did not inhibit other P450s (IC(50) values > 30 microM). There also was no time-dependent inhibition of CYP3A4/5 by bortezomib or its major metabolites. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

硼替佐米通过其硼酸基团与蛋白酶体结合，因此，存在这种基团是实现对蛋白酶体抑制的必要条件。通过对接受单次静脉注射硼替佐米的患者的血浆中的代谢物进行液相色谱/质谱（LC/MS）和液相色谱/串联质谱（LC/MS/MS）的鉴定和表征，确定了代谢物。通过LC/MS/MS和高场核磁共振光谱（NMR）合成和表征的代谢物标准品用于确认代谢物结构。观察到的主体生物转化途径是氧化脱硼，尤其是形成一对对映异构的碳醇酰胺代谢物。亮氨酸和苯丙氨酸部分的进一步代谢产生了三级羟基化代谢物和在苄基位置羟基化的代谢物。还观察到碳醇酰胺转化为相应的酰胺和羧酸。人肝微粒体充分模拟了硼替佐米的体内代谢，因为主要的循环代谢物在体外观察到。使用cDNA表达的细胞色素P450同工酶，确定了几个同工酶参与了硼替佐米的代谢，包括CYP3A4、CYP2C19、CYP1A2、CYP2D6和CYP2C9。

... Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (NMR) were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib, as the principal circulating metabolites were observed in vitro. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模的临床试验中，使用硼替佐米的患者中，血清转氨酶水平升高是常见的，约10%的患者出现这种情况。然而，超过正常上限（ULN）5倍以上的值是罕见的。 硼替佐米通常与其他化疗药物一起使用，包括环磷酰胺和地塞米松，这些药物可能导致乙型肝炎的再激活。然而，尚未有报告特别归因于硼替佐米单独使用导致的乙型肝炎再激活。 可能性评分：C（可能是临床上明显的药物诱导肝损伤的原因）。

In large clinical trials of bortezomib, elevations in serum aminotransferase levels were common, occurring in ~10% of patients. However, values greater than 5 times the upper limit of normal (ULN) were rare, occurring in Bortezomib is typically given with other chemotherapeutic agents including cyclophosphamide and dexamethasone which can cause reactivation of hepatitis B. However, there have been no reports of reactivation of hepatitis B specifically attributable to bortezomib alone. Likelihood score: C (probable cause of clinically apparent drug induced liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

硼替佐米

Compound:bortezomib

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最值得关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

静脉给药1 mg/m2和1.3 mg/m2剂量后，硼替佐米的平均Cmax分别为57和112 ng/mL。在每周两次的给药方案中，1 mg/m2剂量的Cmax范围为67至106 ng/mL，1.3 mg/m2剂量的Cmax范围为89至120 ng/mL。在多发性骨髓瘤患者中，硼替佐米经皮下给药后的Cmax低于静脉给药的剂量；然而，两种给药途径的药物总系统暴露量是等效的。药物血浆浓度在患者之间存在较大的变异性。

Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses, the mean Cmax of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the Cmax ranged from 67 to 106 ng/mL at the dose of 1 mg/m2 and 89 to 120 ng/mL for the 1.3 mg/m2 dose. In patients with multiple myeloma, the Cmax of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations.

来源:DrugBank

吸收、分配和排泄

• 消除途径

硼替佐米通过肾脏和肝脏两条途径消除。

Bortezomib is eliminated by both renal and hepatic routes.

来源:DrugBank

吸收、分配和排泄

• 分布容积

硼替佐米在多发性骨髓瘤患者中的平均分布容积约为498至1884升/平方米，这些患者在单次或重复给药1毫克/平方米或1.3毫克/平方米的剂量下。硼替佐米几乎分布到所有组织中，除了脂肪和脑组织。

The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m² in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m² or 1.3 mg/m². Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue.

来源:DrugBank

吸收、分配和排泄

• 清除

在给予首次剂量1 mg/m²和1.3 mg/m²后，平均总体清除率分别为102 L/h和112 L/h。随后给予1 mg/m²和1.3 mg/m²的剂量后，清除率分别为15 L/h和32 L/h。

Following the administration of a first dose of 1 mg/m² and 1.3 mg/m², the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m², respectively.

来源:DrugBank

吸收、分配和排泄

在给予24名多发性骨髓瘤患者静脉注射1 mg/平方米和1.3 mg/平方米剂量的硼替佐米后（每个剂量水平各12名患者），第一次给药（第1天）后硼替佐米的平均最大血浆浓度（Cmax）分别为57和112 ng/mL。

Following intravenous administration of 1 mg/sq m and 1.3 mg/sq m doses to 24 patients with multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1
• 安全说明：
  S26,S36/37/39
• 危险类别码：
  R23/24/25,R48/23/24/25
• 海关编码：
  2934999090
• 危险品运输编号：
  3261
• RTECS号：
  ED7771666
• 危险类别：
  6.1
• 包装等级：
  II
• 危险性防范说明：
  P260,P301+P310,P304+P340,P320,P330,P361,P405,P501
• 危险性描述：
  H300,H310,H330,H372
• 储存条件：
  Hygroscopic, stored at -20°C in a freezer under an inert atmosphere.

制备方法与用途

根据您提供的信息，我可以总结一下关于硼替佐米（Bortezomib）的关键点：

1. 适应症与生物活性：

   • 硼替佐米是第一个应用于临床的蛋白酶体抑制剂。
   • 它可抑制NF-κB并诱导ERK的磷酸化，从而抑制cathepsin B并在某些肿瘤中抑制自噬。

2. 目标作用机制：

   • 可逆性地抑制20S蛋白酶体的功能
   • 导致蛋白堆积，细胞凋亡

3. 临床应用：

   • 第二线治疗多发性骨髓瘤和套细胞淋巴瘤
   • 对其他多种癌症也有一定的疗效

4. 不良反应与禁忌症：

   • 最常见不良反应：恶心、疲劳、腹泻等
   • 禁用于严重肝损害或对硼替佐米过敏的患者

5. 体外研究结果：

   • 抑制PC-3细胞增殖和诱导细胞凋亡
   • 对多种癌细胞系具有抑制作用

6. 体内研究结果：

   • 在多个癌症模型中均显示出抗癌效果，包括多发性骨髓瘤、肺癌、乳腺癌等

7. 药物特性：

   • 是一种硼酸二肽化合物
   • 口服吸收较差，通常通过注射给药

反应信息

• 作为反应物：
  描述：

  硼替佐米 在 水 作用下， 以 甲醇 为溶剂， 以3.5 g的产率得到bortezomib monohydrate
  参考文献：
  名称：

  CRYSTALLINE BORTEZOMIB PROCESS

  摘要：

  本发明提供了一种制备晶体硼替佐米（Ia）单水合物的方法，该单水合物被指定为晶体形式-SB，并具有水含量范围在3.5-6.0% w/w之间；X射线粉末衍射图谱包括从XRPD峰集中选择的特征20°峰，其选择的峰为5.6、7.5、9.8、10.2、11.3、15.1、18.0、20.5、21.5和23.6±0.20 2θ°，其中9.8和11.39±0.20 2θ°的峰未分裂，100%强度峰存在于5.6±0.20 2θ°处，DSC等温线包括在45至60°C（峰-1）和175至185°C（峰-2）之间的放热峰，以及近似于3387 cm-1、3304 cm-1、2953 cm-1、2927 cm-1、2868 cm-1、1627 cm-1、1455 cm-1、1400 cm-1、1201 cm-1、1150 cm-1、1020 cm-1、747 cm-1和702 cm-1的红外吸收特征峰，和拉曼吸收光谱具有大约在3066 cm-1、1583 cm-1、1528 cm-1、1281 cm-1、1213 cm-1、1035 cm-1、1022 cm-1和1004 cm-1的特征峰。本发明还提供了将所述晶体形式-SB用作治疗癌症的药物组合物中的活性药物成分的用途。

  公开号：

  US20150259364A1
• 作为产物：
  描述：

  (2S)-N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide 在 盐酸 作用下， 以 甲醇 、 水 为溶剂， 以82.3%的产率得到硼替佐米
  参考文献：
  名称：

  Proteasome inhibitor delanzomib for use in the treatment of lupus

  摘要：

  本发明提供了一种治疗狼疮的方法，包括向受试者施用化合物A的步骤。

  公开号：

  US09340559B2

文献信息

• Virtues of Volatility: A Facile Transesterification Approach to Boronic Acids
  作者：Stefan P. A. Hinkes、Christian D. P. Klein

  DOI：10.1021/acs.orglett.9b00584

  日期：2019.5.3

  Boronic acids are an increasingly important compound class for many applications, including C–C bond formation reactions, medicinal chemistry, and diagnostics. The deprotection of boronic ester intermediates is frequently a problematic and inefficient step in boronic acid syntheses. We describe an approach that highly facilitates this transformation by leveraging the volatility of methylboronic acid and

  硼酸对于许多应用而言，都是越来越重要的化合物类别，包括C–C键形成反应，药物化学和诊断学。硼酸酯中间体的脱保护在硼酸合成中通常是一个有问题且效率低下的步骤。我们描述了一种通过利用甲基硼酸及其二醇酯的挥发性极大地促进这种转变的方法。该方法在温和条件下进行，提供了高收率，并且消除了繁琐且麻烦的纯化步骤。
• [EN] TARGETED THERAPEUTICS<br/>[FR] THÉRAPEUTIQUE CIBLÉE
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2015038649A1

  公开（公告）日：2015-03-19

  The present invention provides pharmacological compounds including an effector moiety conjugated to a binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.

  本发明提供了包括与将效应子导向至感兴趣的生物靶点的结合基团共轭的药理化合物。同样，本发明提供了包括这些化合物的组合物、试剂盒和方法（例如治疗、诊断和成像）。这些化合物可以被描述为蛋白质相互作用结合基团-药物共轭（SDC-TRAP）化合物，其中包括蛋白质相互作用结合基团和效应子。例如，在针对治疗癌症的某些实施方式中，SDC-TRAP可以包括Hsp90抑制剂共轭到细胞毒性药剂作为效应子。
• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF BORONIC ACID ESTERS<br/>[FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION D'ESTERS D'ACIDE BORONIQUE
  申请人：FRESENIUS KABI ONCOLOGY LTD

  公开号：WO2018150386A1

  公开（公告）日：2018-08-23

  The present invention relates to an improved process for the preparation of a compound of formula (I), wherein PG1 may be independently selected from tert-butyloxycarbonyl (Boc), phthaloyl, 9-fluorenylmethyloxycarbonyl (Fmoc), triphenylmethyl (Trityl), carboxybenzyl (Cbz), trifluoroacetyl, benzyl (Bn), benzylidene, methanesulfonyl (Mesyl), toluene sulfonyl (Tosyl) or acyl; its isolation as solid and use for the preparation of the compound of formula (IV), in particular the compound of formula (IV) i.e. [(1R)-3-methyl-1[[(2S)-1-oxo-3-phenyl-2- [(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid with more than 99.95% chiral purity, as measured by HPLC.

  本发明涉及一种改进的制备化合物的方法，该化合物的化学式为（I），其中PG1可以独立地选择自叔丁氧羰基（Boc）、邻苯二甲酰基、9-芴甲氧羰基（Fmoc）、三苯甲基（Trityl）、羧苄基（Cbz）、三氟乙酰基、苄基（Bn）、苄亚甲基、甲磺酰基（Mesyl）、甲苯磺酰基（Tosyl）或酰基；其固体分离和用于制备化合物的用途，特别是化合物的化学式（IV），即[(1R)-3-甲基-1-[(2S)-1-氧代-3-苯基-2-[(吡嗪羰基)氨基]丙基]氨基丁基]硼酸，其手性纯度超过99.95%，通过HPLC测量。
• COMPOSITIONS AND METHODS FOR TREATMENT OF AUTOIMMUNE AND OTHER DISEASE
  申请人：CERULEAN PHARMA INC.

  公开号：US20180193486A1

  公开（公告）日：2018-07-12

  Provided are methods relating to the use of CDP-therapeutic agent conjugates for the treatment of autoimmune disease, inflammatory disease, or cancer. Also provided are CDP-therapeutic agent conjugates, particles comprising CDP-therapeutic agent conjugates, and compositions comprising CDP-therapeutic agent conjugates.

  提供了关于使用CDP-治疗剂偶联物治疗自身免疫疾病、炎症性疾病或癌症的方法。还提供了CDP-治疗剂偶联物、包含CDP-治疗剂偶联物的颗粒以及包含CDP-治疗剂偶联物的组合物。
• [EN] BORONIC ESTER PRODRUGS AND USES THEREOF<br/>[FR] PROMÉDICAMENTS D'ESTER BORONIQUE ET LEURS UTILISATIONS
  申请人：MASSACHUSETTS INST TECHNOLOGY

  公开号：WO2020236253A1

  公开（公告）日：2020-11-26

  Disclosed herein are compounds of Formula (I) or (II). The compounds include an agent (e.g., pharmaceutical agent, cosmetic agent, or nutraceutical agent) through a linker that includes a boronic ester moiety in the backbone of the linker. The compounds may be monomers. Also provided are polymers prepared by polymerizing the monomers. The polymers may be useful for delivering the agent to a subject, tissue, biological sample, or a cell. Also provided are methods of preparing the polymers, compositions and kits comprising the polymers, and methods of use (e.g., use in delivering the agent, treating a disease, preventing a disease, diagnosing a disease) involving the polymers or compositions. The structure of the boronic ester moiety may be fine tuned so that the properties related to delivery to a subject, biological sample, tissue, or cell may be fine tuned.

  本文披露了化合物的化学式(I)或(II)。这些化合物包括通过含有硼酸酯基团的连接剂（例如，药物剂、化妆品剂或营养剂）连接的活性物质。这些化合物可以是单体。还提供了通过聚合单体制备的聚合物。这些聚合物可能用于将活性物质传递给受试者、组织、生物样本或细胞。还提供了制备这些聚合物的方法、包含这些聚合物的组合物和试剂盒，以及涉及这些聚合物或组合物的使用方法（例如，用于传递活性物质、治疗疾病、预防疾病、诊断疾病）。硼酸酯基团的结构可以进行微调，以便微调与传递给受试者、生物样本、组织或细胞相关的性质。