Cozaar | 124750-99-8

• 物质功能分类: 原料药 - 循环系统用药 - 抗高血压病药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Cozaar
• 英文别名: [2-butyl-5-chloro-3-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
• CAS: 124750-99-8
• 化学式: C22H22ClN6O-
• 分子量: 421.9
• InChiKey: MDMTUGIZSFHDIC-UHFFFAOYSA-N

物化性质

• 熔点：
  263-265°C
• 溶解度：
  易溶于水和甲醇，微溶于乙腈。

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  77.7
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S36/37/39
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 海关编码：
  2933290090
• RTECS号：
  NI6755100
• 包装等级：
  II
• 危险类别：
  4.1
• 危险性防范说明：
  P240,P210,P241,P264,P280,P302+P352,P370+P378,P337+P313,P305+P351+P338,P362+P364,P332+P313
• 危险品运输编号：
  1325
• 危险性描述：
  H228,H315,H319

制备方法与用途

氯沙坦钾

氯沙坦钾是一种新型非肽类血管紧张素Ⅱ受体（AT1）拮抗剂，在体内代谢生成的EXP3174比母药活性更强、作用更持久。氯沙坦和EXP3174的半衰期分别为2.2小时和6.7小时。该药物具有良好的抗高血压作用，还能够保护心、肾、脑，并逆转心肌和血管壁肥厚，同时排钠利尿及促进尿酸排泄等。不良反应发生率低，病人耐受性良好。

国内主要生产厂家包括杭州默沙东制药有限公司、浙江华海药业股份有限公司和扬子江药业集团四川海蓉药业。其临床应用如下：

1. 治疗原发性高血压：可单用或与其它抗高血压药（如利尿药）合用。
2. 治疗心力衰竭：可单用或与强心药、利尿药合用。
3. 预防高血压伴左心室肥厚患者发生脑卒中。
4. 用于减慢伴有肾病和高血压的2型糖尿病患者的肾病进程。

用法用量

杭州默沙东制药有限公司生产的氯沙坦钾片治疗原发性高血压的用法与用量如下：

• 药品规格: 50mg*7片
• 其他名称: 科莱亚、科素亚、科索亚、芦沙坦、芦沙坦钾、氯沙坦、洛沙坦、洛沙坦钾
• 使用方法：可与其他抗高血压药物一起使用；可与食物同时服用。
• 起始剂量: 血容量减少的病人开始应用时可能出现低血压，可减少起始用量至10mg。
• 常规剂量: 对大多数病人，通常起始和维持剂量为每天一次50mg。治疗3至6周可达到最大降压效果。
• 增加剂量: 在部分病人中，剂量增加到每天一次100mg可产生进一步的降压作用。
• 特殊人群:
  • 血容量不足（例如应用大剂量利尿剂治疗）的病人：起始剂量25mg。
  • 老年病人或肾损害病人包括透析者：不必调整起始剂量。有肝功能损害病史的病人应考虑使用较低剂量。

药物相互作用

1. 氢氯噻嗪、地高辛、华法令、西米替丁、苯巴比妥、酮康唑和红霉素与氯沙坦钾合用时，不具有临床意义上的药物相互作用。
2. 利福平和氟康唑可降低活性代谢产物水平。这些相互作用的临床结果尚未得到评价。
3. 与其他抑制血管紧张素II及其作用的药物一样，本品与保钾利尿药（如：螺内酯、氨苯蝶啶、阿米洛利）、补钾剂或含钾的盐代用品合用时，可导致血钾升高。
4. 同其他抗高血压药物一样，非甾体抗炎药吲哚美辛可降低氯沙坦的抗高血压作用。

生物活性

**Losartan Potassium (DuP 753, MK 954)**是一种血管紧张素II受体拮抗剂，与血管紧张素II竞争性结合AT1受体，IC50为20 nM。

靶点

• 靶标: AT1受体；值: 20 nM

体内研究

在患有由饮食引起的高胆固醇血症的猴子中，Losartan降低低密度脂蛋白在体外氧化的敏感性、单核细胞趋化蛋白-1的血清水平以及循环单核细胞CD11b的表达。在怀孕的小鼠中，Losartan显著抑制了动脉粥样硬化的发展和小鼠低密度脂蛋白对脂肪氧化的敏感性。此外，在雄性Sprague Dawley大鼠中，Losartan增加血管紧张素水平而不改变血液BK水平，并显著降低了血浆肾素活性，同时减少了血浆血管紧张素水平。

通过这些研究可以看出，氯沙坦钾在高血压及其他心血管疾病中的治疗具有广泛的应用前景。

反应信息

• 作为反应物：
  描述：

  Cozaar 、 UDP-alpha-D-glucuronate(3-) 生成 losartan-1-N-beta-D-glucuronide 、 UDP
  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.