candesartan O-glucuronide | 180603-77-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: candesartan O-glucuronide
• 英文别名: candesartan acyl-β-D-glucuronide；Candesartan Acyl-Glucuronide；(2S,3S,4S,5R,6S)-6-[2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carbonyl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid
• CAS: 180603-77-4
• 化学式: C₃₀H₂₈N₆O₉
• 分子量: 616.587
• InChiKey: IQMPSFXZXNRDMY-GMQKQUAPSA-N

物化性质

• 沸点：
  941.1±75.0 °C(Predicted)
• 密度：
  1.62±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  45
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  215
• 氢给体数：
  5
• 氢受体数：
  13

安全信息

• 储存条件：
  -20°C，密封保存于干燥处

制备方法与用途

Candesartan Acyl-Glucuronide 是坎地沙坦的代谢物，具有降压活性。

反应信息

• 作为反应物：
  描述：

  重氮甲烷 、 candesartan O-glucuronide 以 甲醇 、 乙醚 为溶剂， 反应 0.25h， 生成
  参考文献：
  名称：

  化学衍生后，通过液相色谱/电喷雾串联质谱法表征大鼠中新的血管紧张素II受体拮抗剂坎地沙坦西莱克司的共轭代谢产物。

  摘要：

  结合液相色谱和电喷雾质谱（LC / ESI-MS）和串联质谱（MS / MS）来表征新型血管紧张素II受体拮抗剂坎地沙坦cilexetil（TCV-116; （+/-）-1-（环己氧基氧羰基氧基）乙基2-乙氧基-1-[[2'-（1H-四唑-5-基）联苯-4-基]甲基-1H-苯并咪唑-7-羧酸盐）给予药物的大鼠的血浆和胆汁。在大鼠血浆和胆汁中，活性成分MI（坎地沙坦）的葡萄糖醛酸苷是相对于葡萄糖醛酸结合位点的位置异构体。质谱未直接鉴定出MI中的葡萄糖醛酸化位点。然而，通过葡萄糖醛酸苷异构体与重氮甲烷反应制得的二甲基化葡萄糖醛酸苷的MS / MS分析，可以阐明该异构体的结构：血浆中MI的N-葡萄糖醛酸苷（MI-NG）和乙醛酸中的酰基葡萄糖醛酸苷酯（MI-AG）。胆汁。这项研究获得的结果表明，LC / ESI-MS / MS分析通过简单的化学衍生化提供了共轭代谢物的详细结构。

  DOI：

  10.1002/(sici)1096-9888(199608)31:8<873::aid-jms368>3.0.co;2-j
• 作为产物：
  描述：

  坎地沙坦 在 human liver microsomes 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 生成 candesartan N2-glucuronide 、 candesartan O-glucuronide
  参考文献：
  名称：

  The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan

  摘要：

  Losartan, candesartan, and zolarsartan are AT(1) receptor antagonists that inhibit the effect of angiotensin II. We have examined their glucuronidation by liver microsomes from several animals and by recombinant human UDP-glucuronosyltransferases (UGTs). Large differences in the production of different glucuronide regioisomers of the three sartans were observed among liver microsomes from human (HLM), rabbit, rat, pig, moose, and bovine. However, all the liver microsomes produced one or two N-glucuronides in which either N1 or N2 of the tetrazole ring were conjugated. O-Glucuronides were also detected, including acyl glucuronides of zolarsartan and candesartan. Examination of individual human UGTs of subfamilies 1A and 2B revealed that N-glucuronidation activity is widespread, along with variable regioselectivity with respect to the tetrazole nitrogens of these sartans. Interestingly, UGT1A3 exhibited a strong regioselectivity towards the N2 position of the tetrazole ring in all three sartans. Moreover, the tetrazole-N2 of zolarsartan was only conjugated by UGT1A3, whereas the tetrazole-N1 of this aglycone was accessible to other enzymes, including UGT1A5. Zolarsartan O-glucuronide was mainly produced by UGTs 1A10 and 2B7. UGT2B7, alongside UGT1A3, glucuronidated candesartan at the tetrazole-N2 position, whereas UGTs 1A7-1A10 mainly yielded candesartan O-glucuronide. in the case of losartan, no O-glucuronide was generated by any tested human enzyme. Nevertheless, UGTs 1A1, 1A3, 1A10, 2137, and 21317 glucuronidated losartan at the tetrazole-N2, while UGT1A10 also yielded the respective N1-glucuronide. Kinetic analyses revealed that the main contributors to losartan glucuronidation in HLM are UGT1A1 and UGT2B7. The results provide ample new data on substrate specificity in drug glucuronidation. (C) 2008 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2008.07.006

文献信息

• The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan
  作者：Anna Alonen、Moshe Finel、Risto Kostiainen

  DOI：10.1016/j.bcp.2008.07.006

  日期：2008.9

  Losartan, candesartan, and zolarsartan are AT(1) receptor antagonists that inhibit the effect of angiotensin II. We have examined their glucuronidation by liver microsomes from several animals and by recombinant human UDP-glucuronosyltransferases (UGTs). Large differences in the production of different glucuronide regioisomers of the three sartans were observed among liver microsomes from human (HLM), rabbit, rat, pig, moose, and bovine. However, all the liver microsomes produced one or two N-glucuronides in which either N1 or N2 of the tetrazole ring were conjugated. O-Glucuronides were also detected, including acyl glucuronides of zolarsartan and candesartan. Examination of individual human UGTs of subfamilies 1A and 2B revealed that N-glucuronidation activity is widespread, along with variable regioselectivity with respect to the tetrazole nitrogens of these sartans. Interestingly, UGT1A3 exhibited a strong regioselectivity towards the N2 position of the tetrazole ring in all three sartans. Moreover, the tetrazole-N2 of zolarsartan was only conjugated by UGT1A3, whereas the tetrazole-N1 of this aglycone was accessible to other enzymes, including UGT1A5. Zolarsartan O-glucuronide was mainly produced by UGTs 1A10 and 2B7. UGT2B7, alongside UGT1A3, glucuronidated candesartan at the tetrazole-N2 position, whereas UGTs 1A7-1A10 mainly yielded candesartan O-glucuronide. in the case of losartan, no O-glucuronide was generated by any tested human enzyme. Nevertheless, UGTs 1A1, 1A3, 1A10, 2137, and 21317 glucuronidated losartan at the tetrazole-N2, while UGT1A10 also yielded the respective N1-glucuronide. Kinetic analyses revealed that the main contributors to losartan glucuronidation in HLM are UGT1A1 and UGT2B7. The results provide ample new data on substrate specificity in drug glucuronidation. (C) 2008 Elsevier Inc. All rights reserved.
• Characterization of Conjugated Metabolites of a New Angiotensin II Receptor Antagonist, Candesartan Cilexetil, in Rats by Liquid Chromatography/Electrospray Tandem Mass Spectrometry Following Chemical Derivatization
  作者：Takahiro Kondo、Kiyoshi Yoshida、Yoshinobu Yoshimura、Michio Motohashi、Shigeharu Tanayama

  DOI：10.1002/(sici)1096-9888(199608)31:8<873::aid-jms368>3.0.co;2-j

  日期：1996.8

  component, M-I (candesartan), in rat plasma and bile were positional isomers with respect to the binding site of glucuronic acid. The site of glucuronidation in M-I was not directly identified by mass spectrometry. However, the structure of the isomers could be elucidated by the MS/MS analysis of dimethylated glucuronides prepared by the reaction of glucuronide isomers with diazomethane: N-glucuronide

  结合液相色谱和电喷雾质谱（LC / ESI-MS）和串联质谱（MS / MS）来表征新型血管紧张素II受体拮抗剂坎地沙坦cilexetil（TCV-116; （+/-）-1-（环己氧基氧羰基氧基）乙基2-乙氧基-1-[[2'-（1H-四唑-5-基）联苯-4-基]甲基-1H-苯并咪唑-7-羧酸盐）给予药物的大鼠的血浆和胆汁。在大鼠血浆和胆汁中，活性成分MI（坎地沙坦）的葡萄糖醛酸苷是相对于葡萄糖醛酸结合位点的位置异构体。质谱未直接鉴定出MI中的葡萄糖醛酸化位点。然而，通过葡萄糖醛酸苷异构体与重氮甲烷反应制得的二甲基化葡萄糖醛酸苷的MS / MS分析，可以阐明该异构体的结构：血浆中MI的N-葡萄糖醛酸苷（MI-NG）和乙醛酸中的酰基葡萄糖醛酸苷酯（MI-AG）。胆汁。这项研究获得的结果表明，LC / ESI-MS / MS分析通过简单的化学衍生化提供了共轭代谢物的详细结构。