地拉夫定甲磺酸盐 | 147221-93-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 地拉夫定甲磺酸盐
• 中文别名: 甲磺酸地拉韦啶；甲磺酸德拉维定
• 英文名称: Delavirdine Mesylate
• 英文别名: methanesulfonic acid;N-[2-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazine-1-carbonyl]-1H-indol-5-yl]methanesulfonamide
• CAS: 147221-93-0
• 化学式: C23H32N6O6S2
• 分子量: 552.7
• InChiKey: MEPNHSOMXMALDZ-UHFFFAOYSA-N

物化性质

• 熔点：
  118-120°C
• 溶解度：
  二甲基亚砜：>5mg/mL
• 颜色/状态：
  White to tan crystalline powder
• 气味：
  Odorless

计算性质

• 辛醇/水分配系数(LogP)：
  2.22
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  182
• 氢给体数：
  4
• 氢受体数：
  10

ADMET

代谢

Delavirdine与血浆蛋白广泛结合，主要通过CYP3A4代谢。主要的代谢途径是N-脱烷基化。由于CYP3A活性的差异，受试者之间Delavirdine的血浆浓度存在相当大的个体间变异性。脑脊液与血浆的比例是0.02。

Delavirdine binds extensively to plasma proteins and primarily is metabolized by CYP3A4. The major metabolic pathway results in N-dealkylation. There is considerable intersubject variability in plasma delavirdine concentrations related to differences in CYP3A activity. The CSF-to-plasma ratio is 0.02.

来源:Hazardous Substances Data Bank (HSDB)

代谢

地拉韦定的代谢在小鼠体内是广泛的，涉及酰胺键断裂、N-脱烷基化、吡啶环C-6'位置的羟基化以及吡啶环裂解，这些通过质谱和/或1H和13C核磁共振光谱确定。在低药物剂量下，N-脱烷基化和酰胺键断裂是主要的代谢途径，当地拉韦定转化为脱烷基地拉韦定的生物转化达到饱和或受到抑制时，在高剂量和多次给药后，酰胺键断裂成为主要的代谢途径。

The metabolism of delavirdine in the mouse was extensive and involved amide bond cleavage, N-desalkylation, hydroxylation at the C-6' position of the pyridine ring, and pyridine ring-cleavage as determined by MS and/or 1H and 13C NMR spectroscopies. N-desalkylation and amide bond cleavage were the primary metabolic pathways at low drug doses and, as the biotransformation of delavirdine to desalkyl delavirdine reached saturation or inhibition, amide bond cleavage became the predominant pathway at higher doses and after multiple doses.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

乳哺期使用概要：Delavirdine 在美国已不再销售。没有关于在哺乳期间使用 Delavirdine 的已发表信息。在美国和其他可以获取清洁水源和负担得起的替代喂养方式的国家，建议感染 HIV 的母亲不要哺乳，以避免产后传播 HIV-1 感染。不建议在哺乳期间使用 Delavirdine。 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发表信息。 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发表信息。

◉ Summary of Use during Lactation:Delavirdine is no longer marketed in the US No published information is available on the use of delavirdine during breastfeeding. In the US and other countries where access to clean water and affordable replacement feeding are available, it is recommended that mothers living with HIV not breastfeed their infants to avoid postnatal transmission of HIV-1 infection. Delavirdine is not recommended during breastfeeding. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

可能由于delavirdine抑制CYP同工酶3A和2C9的作用，与阿米替林、阿司咪唑、苯二氮卓类药物、钙通道阻滞剂、西沙必利、麦角衍生物或特非那定同时使用可能会导致严重甚至威胁生命的副作用；建议在患者使用delavirdine期间对这些药物的剂量进行调整，或者使用替代药物。

Concurrent administration of amphetamines, astemizole, benzodiazepines, calcium channel blocking agents, cisapride, ergot derivatives, or terfenadine with delavirdine may result in potentially serious and/or life-threatening adverse events as a result of the inhibitory effect of delavirdine on CYP isoenzymes 3A and 2C9; it is recommended that dosage adjustments be made for these medications, or that alternative medications be used, while patients are taking delavirdine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用Delavirdine 300毫克与铝镁口服悬浮液，会使得Delavirdine的AUC（药时曲线下面积）降低41 ± 19%；应建议患者在服用Delavirdine前后1小时内不要使用抗酸药。

Concurrent administration of delavirdine 300 mg with aluminum and magnesium oral suspension decreases AUC for delavirdine by 41 + or - 19%; patients should be advised not to take antacids within 1 hour of taking delavirdine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用delavirdine与卡马西平、苯巴比妥或苯妥英会显著降低delavirdine的谷底血浆浓度；不建议同时使用。

Concurrent use of delavirdine with carbamazepine, phenobarbital, or phenytoin substantially decreases the trough plasma concentration of delavirdine; concurrent use is not recommended.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

西咪替丁、法莫替丁、尼扎替丁和雷尼替丁可以提高胃部pH值，可能会减少地拉韦定的吸收；不建议这些药物与地拉韦定长期联用。

Cimetidine, famotidine, nizatidine, and ranitidine increase gastric pH and may reduce absorption of delavirdine; long-term use of these medications with delavirdine is not recommended.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：粪便：健康志愿者每天三次服用330毫克多剂后，粪便中占44%。肾脏：健康志愿者每天三次服用330毫克多剂后，肾脏中占51%。小于5%的剂量以未改变的形式在尿液中回收。

Elimination: Fecal: 44% following multiple doses of 330 mg three times a day in healthy volunteers. Renal: 51%, following multiple doses of 330 mg three times a day in healthy volunteers. Less than 5% of the dose is recovered unchanged in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Delavirdine 主要分布在血液血浆中。

Delavirdine is distributed predominantly into blood plasma.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Delavirdine 吸收良好，特别是在 pH 小于 2.0 时。

Delavirdine is well absorbed, especially at pH less than 2.0.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫酸地拉韦定在口服给药后迅速吸收，给药后大约1小时达到药物血浆浓度峰值。在HIV感染的成年人中，口服给予400毫克硫酸地拉韦定，每日三次，药物的平均稳态峰值血浆浓度为15.98微克/毫升（范围：0.91-45.66微克/毫升），平均谷值血浆浓度为6.85微克/毫升（范围：0.05-20.55微克/毫升），平均药时曲线下面积（AUC）为82.19微克·小时/毫升。

Delavirdine mesylate is rapidly absorbed following oral administration, and peak plasma concentrations of the drug are attained approximately 1 hour after the dose. Following oral administration of 400 mg of delavirdine mesylate 3 times daily in HIV-infected adults, mean steady-state peak plasma concentrations of the drug are 15.98 ug/ml (range: 0.91-45.66 ug/ml), mean trough plasma concentrations are 6.85 ug/ml (range: 0.05-20.55 ug/ml), and mean AUC is 82.19 ughour/ml.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品运输编号：
  NONH for all modes of transport
• WGK Germany：
  3
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P201,P202,P261,P264,P270,P271,P280,P363,P405,P501
• 危险性描述：
  H315,H319,H360

制备方法与用途

生物活性

Delavirdine Mesylate 是 delavirdine 的甲磺酸盐形式。Delavirdine 是一种合成的、非核苷类逆转录酶抑制剂。

靶点

Target	Value
HIV1 RT	0.26 μM

体外研究

Delavirdine 是有效的、选择性 HIV1 逆转录酶抑制剂，IC50 值为 0.26 μM。在浓度为 100 μM 的情况下，其对人类淋巴细胞生存能力的降低作用少于 8%，显示出较低的细胞毒性。

体内研究

单剂量给药后，Delavirdine 在大鼠体内的药代动力学呈现非线性关系；在狗中同样表现出非线性的特征。当剂量为 10 mg/kg 时，Delavirdine 在狗中的系统清除率比在大鼠中的低 20 倍，在猴子中的清除率与大鼠相当。在猴、大鼠和狗中，口服生物利用度依次升高，分别为 30%、65% 和 100%。

文献信息

• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。
• [EN] AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION<br/>[FR] DÉGRONIMÈRES DE C3-GLUTARIMIDE LIÉS À UNE AMINE POUR LA DÉGRADATION DE PROTÉINES CIBLES
  申请人：C4 THERAPEUTICS INC

  公开号：WO2017197051A1

  公开（公告）日：2017-11-16

  This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.

  这项发明提供了胺连接的C3-戊二酰亚胺Degronimers和Degrons，用于治疗应用，如本文进一步描述的，以及它们的使用方法、组合物以及它们的制备方法。
• [EN] TRICYCLIC TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY<br/>[FR] COMPOSÉS TRIAZOLES TRICYCLIQUES MODULANT L'ACTIVITÉ HSP90
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2009139916A1

  公开（公告）日：2009-11-19

  The present invention relates to substituted tricyclic triazole compounds and compositions comprising substituted tricyclic triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

  本发明涉及替代三环三唑化合物和包含替代三环三唑化合物的组合物。该发明还涉及在需要的受体中抑制Hsp90活性的方法，以及预防或治疗高增殖性疾病（如癌症）的方法，其中包括向受体施用本发明的化合物或包含这种化合物的组合物。
• [EN] PYRIDINE CARBOXAMIDE AND METHODS FOR INHIBITING HIV INTEGRASE<br/>[FR] CARBOXAMIDE DE PYRIDINE ET METHODES PERMETTANT D'INHIBER L'INTEGRASE DU VIH
  申请人：VIROCHEM PHARMA INC

  公开号：WO2005042524A1

  公开（公告）日：2005-05-12

  Compounds of formula (I): wherein R1, R2, R4, R10, R11, and Q are as defined herein, and their pharmaceutically acceptable salts, are useful in the prevention or treatment of HIV infections.

  式(I)的化合物：其中R1、R2、R4、R10、R11和Q如本文所定义，并且它们的药用盐，在预防或治疗HIV感染方面是有用的。
• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。