莫达非尼 | 68693-11-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 莫达非尼
• 中文别名: 莫达非；莫达芬尼；2-[(二苯甲基)亚砜基]乙酰胺
• 英文名称: Modafinil
• 英文别名: 2-benzhydrylsulfinylacetamide
• CAS: 68693-11-8
• 化学式: C₁₅H₁₅NO₂S
• mdl: MFCD00868082
• 分子量: 273.356
• InChiKey: YFGHCGITMMYXAQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.133
• 拓扑面积：
  79.4
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

主要消除途径是代谢（大约90%），主要由肝脏进行，随后是肾消除代谢物。尿液碱化对莫达非尼的消除没有影响。代谢通过水解脱氨、S-氧化、芳香环羟基化和葡萄糖醛酸结合进行。不到10%的给药剂量以原形药物形式排出。在一项使用放射性标记莫达非尼的临床研究中，给药后11天内回收了81%的放射性活性，主要在尿液中（80%对1.0%在粪便中）。尿液中药物的最大部分是莫达非尼酸，但至少还有六种其他代谢物以较低浓度存在。只有两种代谢物在血浆中达到可观的浓度，即莫达非尼酸和莫达非尼磺酮。在临床前模型中，莫达非尼酸、莫达非尼磺酮、2-((二苯甲基)磺酰基)乙酸和4-羟基莫达非尼无效或似乎不介导莫达非尼的觉醒作用。

The major route of elimination is metabolism (approximately 90%), primarily by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of modafinil. Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a clinical study using radiolabeled modafinil, a total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces). The largest fraction of the drug in urine was modafinil acid but at least six other metabolites were present in lower concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models, modafinil acid, modafinil sulfone, 2-((diphenylmethyl)sulfonyl)acetic acid and 4-hydroxy modafinil, were inactive or did not appear to mediate the arousal effects of modafinil.

来源:Hazardous Substances Data Bank (HSDB)

代谢

根据体外数据，莫达非尼部分通过肝脏细胞色素P450的3A亚型（CYP3A4）进行代谢。

Based on in vitro data, modafinil is metabolized partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4).

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏 消除途径：主要的消除途径是代谢（约占90%），主要由肝脏进行，随后通过肾脏消除代谢物。 半衰期：23-215小时

Hepatic Route of Elimination: The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites. Half Life: 23-215 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

尽管确切的机制尚不清楚，但体外研究表明，莫达非尼尔通过结合多巴胺再摄取泵，抑制多巴胺的再摄取，导致细胞外多巴胺的增加。莫达非尼尔激活谷氨酸能回路同时抑制GABA。由于缺乏任何显著愉悦或愉快的效果，莫达非尼尔被认为比其他兴奋剂具有更少的滥用潜力。莫达非尼尔可能通过包括直接抑制多巴胺再摄取、间接抑制VLPO中的去甲肾上腺素再摄取和激活食欲素的协同机制组合发挥作用。莫达非尼尔通过直接刺激受体，具有部分α1B-肾上腺素能激动剂效果。

The exact mechanism of action is unclear, although <i>in vitro</i> studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：莫达非尼尔

Compound:modafinil

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后迅速吸收。

Rapid following oral administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

主要消除途径是代谢（约90%），主要由肝脏进行，随后通过肾脏消除代谢物。

The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.9升/千克

0.9 L/kg

来源:DrugBank

吸收、分配和排泄

这是一项开放标签、单中心、单次给药、平行组的研究，在健康的年轻男性和女性以及健康的老年男性中进行了，以探讨年龄和性别对单次口服200毫克莫达非尼尔片后药代动力学的影响。每组各纳入12名受试者：年轻男性、年轻女性和老年男性。每个受试者在空腹（隔夜）状态下接受了2片100毫克的莫达非尼尔片。在给药后长达72小时内，收集血液和尿液样本，以测定莫达非尼尔及其酸和砜代谢物在血浆和尿液中的水平。还确定了个体对映异构体，即d-和l-莫达非尼尔的血浆浓度。药代动力学参数通过非房室模型方法确定。... 莫达非尼尔在口服给药后迅速吸收，并缓慢从体内清除（半衰期大约为11-14小时）。莫达非尼尔酸是主要的尿液代谢物，占剂量的35%至60%。这项研究的结果表明，年龄和性别影响了莫达非尼尔的清除过程。在这方面，男性对莫达非尼尔的清除率随着年龄的增长而降低，而年轻女性对莫达非尼尔的清除速度比年轻男性快。莫达非尼尔的立体特异性药代动力学也得到了证实。d-莫达非尼尔的消除速度是l-莫达非尼尔的3倍。

An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. ... Modafinil was rapidly absorbed after oral dosing and slowly cleared (half life approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚不清楚莫达非尼或其代谢物是否会分布到乳汁中。

It is not known whether modafinil or its metabolites are distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  莫达非尼 在 lithium hydroxide monohydrate 、 水 、 lithium tert-butoxide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 乙腈 为溶剂， 反应 6.42h， 生成 (E)-4-[(2-benzhydrylsulfinylacetyl)amino]-4-oxobut-2-enoic acid
  参考文献：
  名称：

  COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DEGENERATIVE DISORDERS AND NEUROLOGICAL DISEASES

  摘要：

  该发明涉及公式I的化合物或其药用可接受的盐，以及其多晶型、溶剂合物、对映体、立体异构体和水合物。包含公式I化合物的有效量的药物组合物，以及用于治疗神经退行性疾病和神经疾病的方法，可以制备成口服、颊内、直肠、局部、经皮、经粘膜、静脉内、肠外给药、糖浆或注射剂。这些组合物可用于治疗嗜睡症、轮班工作睡眠障碍，并作为阻塞性睡眠呼吸暂停/减少症、嗜睡症（如特发性嗜睡症）、精神/神经退行性疾病、注意力缺陷多动障碍、精神/神经退行性疾病、人格解体障碍、认知增强、疲劳、化疗后认知障碍和体重减轻的辅助治疗。

  公开号：

  US20150141513A1
• 作为产物：
  描述：

  2-二苯基甲基亚砜基乙酸 在 ammonium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 莫达非尼
  参考文献：
  名称：

  Simple Synthesis of Modafinil Derivatives and Their Anti-inflammatory Activity

  摘要：

  描述了莫达非尼衍生物的简单合成及其生物活性。关键的合成策略包括取代反应和偶联反应。我们通过测量在LPS刺激后硝酸盐产生的抑制和iNOS及COX-2的表达，确定了莫达非尼衍生物在培养的BV2细胞中的抗炎效果。研究发现，对于硫化物类似物，在酰胺部分引入脂肪族基团（化合物11a–d）导致其抗炎活性低于环状或芳香族部分（化合物11e–k）。然而，对于亚磺酸酯类似物，引入脂肪族部分（化合物12a–d）在BV-2小胶质细胞中显示出比环状或芳香族片段（化合物12e–k）更高的抗炎活性。

  DOI：

  10.3390/molecules170910446

文献信息

• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• Biaryl-methanethio-, -sulphinyl- and sulphonyl derivatives
  申请人：CEPHALON, INC.

  公开号：EP1586559A1

  公开（公告）日：2005-10-19

  FIELD OF THE INVENTION The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions that include substituted biaryl-methanesulfinyl acetamides of Formula (I): wherein Ar, Y, R1, R2, R4, R5, q and x are as defined herein; and their use in the treatment of diseases, including treatment of sleepiness associated with narcolepsy, obstructive sleep apnea, or shift work disorder; Parkinson's disease; Alzheimer's disease; attention deficit disorder; attention deficit hyperactivity disorder; depression; or fatigue associated with a neurological disease; as well as the promotion of wakefulness.

  本发明涉及化学组合物、其制备方法以及组合物的用途。特别是，本发明涉及包括式（I）的取代联苯基-甲磺酰基乙酰胺的组合物： 其中Ar、Y、R1、R2、R4、R5、q和x如本文所定义；以及它们在治疗疾病中的用途，包括治疗与嗜睡症、阻塞性睡眠呼吸暂停或倒班工作障碍相关的嗜睡症、帕金森病、阿尔茨海默病、注意力缺陷障碍、注意力缺陷多动障碍、抑郁症或与神经系统疾病相关的疲劳，以及促进清醒。