西达尿苷 | 1141397-80-9

• 物质功能分类: 生物化工 - 抑制剂
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 西达尿苷
• 英文名称: cedazuridine
• 英文别名: (4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine；(4R)-1-[(2R, 4R, 5R)-3,3-difluoro-4-hydroxy-5- (hydroxymethyl) oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one；(4R)-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one
• CAS: 1141397-80-9
• 化学式: C₉H₁₄F₂N₂O₅
• 分子量: 268.217
• InChiKey: VUDZSIYXZUYWSC-DBRKOABJSA-N

物化性质

• 沸点：
  597.7±50.0 °C(Predicted)
• 密度：
  1?+-.0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：50 mg/mL（186.42 mM；超声加热并加热至 60°C）
• 熔点：
  162-165

计算性质

• 辛醇/水分配系数(LogP)：
  -1.1
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  102
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

代谢

赛达珠瑞丁（Cedazuridine）的代谢尚未完全明确。已知赛达珠瑞丁会转化为其对映异构体，该对映异构体抑制胞苷脱氨酶的效力大约降低10倍，随后通过未知的途径被降解。[A215107, L14897]

The metabolism of cedazuridine is not well-established. Cedazuridine is known to be converted to an epimer that is roughly 10-fold less effective in inhibiting cytidine deaminase and is subsequently degraded through unknown pathways.[A215107, L14897]

来源:DrugBank

毒理性

• 毒性总结

塞达唑嘧啶通过口服给予小鼠，按照7天连续给药/21天停药的周期，总共91天，剂量为100、300或1000毫克/千克，仅在1000毫克/千克的剂量下产生了异常效果，这个剂量大约是人类推荐剂量的108倍。这些效果包括睾丸、附睾和卵巢的异常组织学改变，以及精子数量的减少；在停止给予塞达唑嘧啶后，这些效果是可逆的。

Cedazuridine administered orally to mice in 7 days on/21 days off cycles for a total of 91 days in doses of 100, 300, or 1000 mg/kg produced abnormal effects only at the 1000 mg/kg dose, which is roughly 108 times the recommended dose in humans. These effects included abnormal histology of the testes, epididymis, and ovaries, as well as decreased sperm count; these effects were reversible following cedazuridine removal.

来源:DrugBank

毒理性

• 蛋白质结合

去甲基化药物[地西他滨]和胞嘧啶类似物[塞达唑瑞啶]的血浆蛋白结合均不明显。在17至342纳克/毫升的剂量范围内，[地西他滨]的结合分数在2%至4%之间，而在1000纳克/毫升至50000纳克/毫升的剂量范围内，[塞达唑瑞啶]的结合分数在2%至6%之间。[L14897]

Neither [decitabine] nor cedazuridine display appreciable plasma protein binding. The bound fraction of [decitabine] between doses of 17 and 342 ng/mL was between 2 and 4%, while that of cedazuridine for doses between 1000 ng/mL and 50000 ng/mL was between 2 and 6%.[L14897]

来源:DrugBank

吸收、分配和排泄

• 吸收

塞达唑啶（100毫克）与[地西他滨]（35毫克）一起口服，每天一次，连续五天，导致[地西他滨]在第1天的AUC和稳态AUC（变异系数）分别为103（55%）和178（53%）ng*hr/mL，塞达唑啶分别为2950（49%）和3291（45%）ng*hr/mL。总的来说，[地西他滨]的5天累积AUC为851（50%）。同样，[地西他滨]和塞达唑啶的Cmax分别为145（55%）和371（52%）ng/mL。中位Tmax为[地西他滨]1小时（范围0.3至3.0小时），塞达唑啶为3小时（范围1.5至6.1小时）。[L14897] 通过比较口服[地西他滨]与塞达唑啶共同给药时的AUC与单独静脉注射[地西他滨]的AUC，评估了[地西他滨]的口服生物利用度，在第1天为60%（90%CI为55-65%）。相应的，在第5天和考虑累积第5天剂量时的值分别为106%（90%CI：98，114）和99%（90%CI：93，106）。因此，[地西他滨]的口服生物利用度在5天的治疗周期中接近100%。[L14897]

Cedazuridine (100 mg) taken orally with [decitabine] (35 mg) once daily for five days resulted in a day 1 AUC and steady-state AUC (coefficient of variation) of 103 (55%) and 178 (53%) ng\*hr/mL for [decitabine] and 2950 (49%) and 3291 (45%) ng\*hr/mL for cedazuridine, respectively. Overall, the 5-day cumulative AUC for [decitabine] was 851 (50%). Similarly, the C_max for [decitabine] and cedazuridine was 145 (55%) and 371 (52%) ng/mL, respectively. The median T_max for [decitabine] was 1 hr (range 0.3 to 3.0 hrs) and for cedazuridine was 3 hrs (range 1.5 to 6.1 hrs).[L14897] The bioavailability of [decitabine], as assessed by comparing the AUC of oral [decitabine] co-administered with cedazuridine to intravenous [decitabine] alone, was 60% on day 1 (90% CI of 55-65%). The corresponding values on day 5 and considering the cumulative day 5 dose were 106% (90% CI: 98, 114) and 99% (90% CI: 93, 106). Hence, the oral bioavailability of [decitabine] approaches 100% over the 5-day treatment cycle.[L14897]

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约 46% 的赛达唑啉出现在尿液中，其中 21% 未发生改变；51% 出现在粪便中，其中 27% 未发生改变。[L14897]

Roughly 46% of cedazuridine is found in urine, 21% of which is unchanged, and 51% is found in feces, 27% of which is unchanged.[L14897]

来源:DrugBank

吸收、分配和排泄

• 分布容积

表观分布容积（及变异系数）[地西他滨]和赛达拉滨在稳态时分别为417 (54%) 和296 (51%)。

The apparent volume of distribution (and coefficient of variation) of [decitabine] and cedazuridine at steady state was 417 (54%) and 296 (51%), respectively.[L14897]

来源:DrugBank

吸收、分配和排泄

• 清除

塞达唑啶的表观稳态清除率为30.3升/小时，变异系数为46%。

Cedazuridine has an apparent steady-state clearance of 30.3 L/hours, with a coefficient of variation of 46%.[L14897]

来源:DrugBank

安全信息

• 储存条件：
  存储温度应控制在2-8°C，并避免光照。

制备方法与用途

cedazuridine（E7727）是一种胞苷脱氨酶(CDA)抑制剂，其IC50值为0.4 μM。

反应信息

• 作为产物：
  描述：

  [(2R,3R,5R)-3-benzoyloxy-5-(2,4-dioxo-1,3-diazinan-1-yl)-4,4-difluorooxolan-2-yl]methyl benzoate 在 cerium(III) chloride heptahydrate 、 氨 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 119.08h， 生成 西达尿苷
  参考文献：
  名称：

  [EN] SYNTHETIC ROUTE TO 2'-DEOXY-2',2'-DIFLUOROTETRAHYDROURIDINES
  [FR] VOIE DE SYNTHÈSE POUR 2'-DÉSOXY-2',2'-DIFLUOROTÉTRAHYDROURIDINES

  摘要：

  本发明涉及合成2'-脱氧-2',2'-二氟四氢尿苷化合物的方法和中间体。

  公开号：

  WO2015066162A1

文献信息

• [EN] 2'-DEOXY-2',2'-DIFLUOROTETRAHYDROURIDINES WITH HIGH PURITY AND METHODS OF MAKING THE SAME<br/>[FR] 2'-DÉSOXY-2',2'-DIFLUOROTÉTRAHYDROURIDINES DE PURETÉ ÉLEVÉE ET LEURS PROCÉDÉS DE FABRICATION
  申请人：OTSUKA PHARMA CO LTD

  公开号：WO2021071890A1

  公开（公告）日：2021-04-15

  The invention relates to methods of synthesizing 2'-deoxy-2',2'-difluorotetrahydrouridine with increased purity and uniform particle size distribution. In particular, methods of the invention include crystallization and isolation procedures rendering synthetic reaction intermediates. The invention further includes compositions comprising the final compound in highly pure form, including lower number of impurities and lower levels of individual and total impurities.

  该发明涉及一种合成2'-去氧-2',2'-二氟四氢尿苷的方法，该方法具有提高纯度和均匀粒径分布的特点。具体而言，该发明的方法包括结晶和分离程序，用于生成合成反应中间体。该发明还包括包含最终化合物的高纯度形式的组合物，其中杂质数量较低，个别和总杂质的水平也较低。
• Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase
  作者：Dana Ferraris、Bridget Duvall、Greg Delahanty、Bipin Mistry、Jesse Alt、Camilo Rojas、Christopher Rowbottom、Kristen Sanders、Edgar Schuck、Kuan-Chun Huang、Sanjeev Redkar、Barbara B. Slusher、Takashi Tsukamoto

  DOI：10.1021/jm401856k

  日期：2014.3.27

  Several 2′-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2′-Deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys

  合成了几种2'-氟化的四氢尿苷衍生物作为胞苷脱氨酶（CDA）的抑制剂。（4R）-2′-脱氧-2′，2′-二氟-3,4,5,6-四氢尿苷（7a）在其N-糖基键上显示出比四氢尿苷（THU）5更高的酸稳定性。结果，与5相比，化合物7a在恒河猴中表现出改善的口服药代动力学特征，血浆暴露量更高且可重现。7a与地西他滨（一种CDA底物）的共同给药可提高恒河猴中地西他滨的血浆水平。这些结果表明，化合物7a中可以作为酸稳定的替代5 作为受CDA介导的新陈代谢作用的药物的药物增强剂。
• [EN] 2 ' -FLU0R0-2 ' -DEOXYTETRAHYDROURIDINES AS CYTIDINE DEAMINASE INHIBITORS<br/>[FR] CERTAINS COMPOSÉS, COMPOSITIONS ET PROCÉDÉS
  申请人：EISAL CORP OF NORTH AMERICA

  公开号：WO2009052287A1

  公开（公告）日：2009-04-23

  The present invention provides certain tetrahydrouridine derivative compounds, pharmaceutical compositions and kits comprising such compounds, and methods of making and using such compounds.

  本发明提供了某些四氢尿嘧啶衍生物化合物、包含这些化合物的药物组合物和试剂盒，以及制备和使用这些化合物的方法。
• Synthetic route to 2′-deoxy-2′,2′-difluorotetrahydrouridines
  申请人：Otsuka Pharmaceutical Co., Ltd.

  公开号：US11028119B2

  公开（公告）日：2021-06-08

  The present invention relates to methods and intermediates for synthesizing 2′-deoxy-2′,2′-difluorotetrahydrouridine compounds.

  本发明涉及合成 2′-脱氧-2′,2′-二氟四氢尿苷化合物的方法和中间体。
• Low dose combination CDA substrate drug/cedazuridine with extended administration
  申请人：Otsuka Pharmaceutical Co., Ltd.

  公开号：US11224610B2

  公开（公告）日：2022-01-18

  This invention relates to methods and compositions for administering an effective amount of a CDA substrate drug and an effective amount of cedazuridine. In particular, the invention relates to methods for treating cancer, inhibiting degradation of a CDA substrate drug, and reducing DNA methylation in a subject in need thereof comprising administering an effective amount of a CDA substrate drug and an effective amount of cedazuridine.

  本发明涉及施用有效量的 CDA 底物药物和有效量的西达脲苷的方法和组合物。特别是，本发明涉及治疗癌症、抑制 CDA 底物药物降解和减少有需要的受试者 DNA 甲基化的方法，包括施用有效量的 CDA 底物药物和有效量的西达脲苷。