艾沙康唑 | 742049-41-8

• 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: 艾沙康唑
• 英文名称: Isavuconazonium
• 英文别名: [2-[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]ethoxycarbonyl-methylamino]pyridin-3-yl]methyl 2-(methylamino)acetate
• CAS: 742049-41-8
• 化学式: C35H35F2N8O5S+
• 分子量: 717.8
• InChiKey: RSWOJTICKMKTER-QXLBVTBOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  51
• 可旋转键数：
  15
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  188
• 氢给体数：
  2
• 氢受体数：
  13

ADMET

代谢

代谢主要发生在肝脏，涉及CYP3A4和CYP3A5的I相代谢，随后通过尿苷二磷酸葡萄糖醛酸基转移酶（UGT）进行修饰。

Metabolism is primarily hepatic, with CYP3A4 and CYP3A5 involved in phase I metabolism, followed by modification by uridine diphosphate glucuronosyltransferase (UGT).

来源:DrugBank

毒理性

• 肝毒性

血清转氨酶水平短暂升高发生在1%至5%的使用伊沙曲康唑的患者中。这些升高通常无症状且自我限制，但偶尔有患者因ALT升高而需要停止使用伊沙曲康唑。临床上明显的肝毒性尚未有报道与伊沙曲康唑有关，但它使用范围有限。其他三唑类药物，如氟康唑和伏立康唑，已经上市超过十年并且被广泛使用，已经与罕见的临床上明显的肝损伤有关。损伤发生在治疗的前几个月内，血清酶升高的模式从胆汁淤积到肝细胞不等。已经报道了几例归因于其他三唑类药物的急性肝衰竭病例。免疫过敏特征和自身抗体不常见。停止治疗后的恢复通常需要6到10周，但在某些情况下，完全解决的时间可能会延长。

Transient elevations in serum aminotransferase levels occur in 1% to 5% of patients on isavuconazonium. These elevations are usually asymptomatic and self-limited, but occasional patients require discontinuation of isavuconazonium because of ALT elevations. Clinically apparent hepatotoxicity has not been reported with isavuconazonium, but it has had limited general use. Other triazoles, such as fluconazole and voriconazole that have been available for more than a decade and have had wide scale use, have been associated with rare instances of clinically apparent liver injury. The injury arises within the first few months of therapy and the pattern of serum enzyme elevations has been variable from cholestatic to hepatocellular. Several cases of acute liver failure attributed to other triazoles have been reported. Immunoallergic features and autoantibodies are uncommon. Recovery upon stopping therapy generally takes 6 to 10 weeks but, in some cases, the time to complete resolution may be prolonged.

来源:LiverTox

毒理性

• 蛋白质结合

大于99%。

>99%

来源:DrugBank

吸收、分配和排泄

• 吸收

静脉注射伊萨伏康唑作为前药时，超过99%的前药会迅速转化为活性伊萨伏康（由血浆酯酶催化）。伊萨伏康唑的口服给药显示98%的口服生物利用度，然而与食物同服会导致药时曲线下面积（AUC）降低20%，同时最大血清浓度（Cmax）降低50%，并且达到Cmax的时间增加1.5小时。

When administered intravenously as isavuconazonium, >99% of the prodrug is quickly converted to active isavuconazole (catalyzed by plasma esterases). Oral administration of isavuconazonium shows 98% oral bioavailability, however administration with food results in a 20% decrease in AUC (area under concentration-time curve) as well as decreasing maximum serum concentration (Cmax) by 50% and increasing time to Cmax by 1.5 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

45%通过粪便和胆汁排出，45%以无活性代谢物形式通过尿液排出。不到1%的活性艾沙康唑以原形通过尿液排出。

45% excreted in feces and bile, and 45% excreted in urine as inactive metabolites. Less than 1% of active isavuconazole is excreted unchanged in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

450升

450 L

来源:DrugBank

文献信息

• N-substituted carbamoyloxyalkyl-azolium derivatives
  申请人：Fukuda Hiroshi

  公开号：US20070027322A1

  公开（公告）日：2007-02-01

  N-substituted carbamoyloxyalkyl-azolium derivatives which have antifungal activity and are useful for the treatment of fungal diseases.

  N-取代的氨基甲酰氧烷基-唑状衍生物具有抗真菌活性，可用于治疗真菌病。
• [EN] METHOD FOR PREPARING ISAVUCONAZONIUM SULFATE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE SULFATE D'ISAVUCONAZONIUM<br/>[ZH] 一种艾沙康唑鎓硫酸盐的制备方法
  申请人：SHANGHAI DESANO BIO PHARMACEUTICAL CO LTD

  公开号：WO2021129580A1

  公开（公告）日：2021-07-01

  提供一种艾沙康唑鎓硫酸盐的制备方法，具体地，涉及的制备方法包括：在提供硫酸氢根离子的化合物的存在下，使式V化合物进行反应，从而得到如式VI所示的艾沙康唑鎓硫酸盐。制备方法具有中间体稳定且易于分离纯化，操作简便，反应收率高，易于工业化生产的优势。
• STABILIZED PHARMACEUTICAL COMPOSITION
  申请人：Ishimoto Hayato

  公开号：US20100249426A1

  公开（公告）日：2010-09-30

  It is an object of the present invention to provide a pharmaceutical composition containing a stable azole-based compound, which is useful as an antifungal agent. According to the present invention, the above-mentioned object can be achieved by adding magnesium hydroxide carbonate, triethylamine, arginine, or another such basic substance to an azole-based compound that is unstable in acids. The above-mentioned pharmaceutical composition is stable enough that the compound will not degrade if the temperature, humidity, or other such conditions should change during production or storage. Also, this composition is useful as a therapeutic agent for deep mycoses because systemic administration is possible by applying it to an oral agent or an injection.
• METHODS FOR PURIFYING ISAVUCONAZONIUM SULFATE
  申请人：Basilea Pharmaceutica International AG

  公开号：US20210323959A1

  公开（公告）日：2021-10-21

  The invention provides methods for purifying isavuconazonium sulfate comprising the steps of —(a) providing a mixture comprising the sulfate salt of the compound of formula (I) and an aliphatic alcohol, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; —(b) allowing a first portion of the sulfate salt of the compound of formula (I) to crystalize from the mixture; and —(c) adding an aprotic organic solvent to the mixture and allowing an additional portion of the sulfate salt of the compound of formula (I) to precipitate from the mixture.
• US7189858B2
  申请人：——

  公开号：US7189858B2

  公开（公告）日：2007-03-13