赖氨酸安非他命二甲磺酸盐 | 608137-32-2

• 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: 赖氨酸安非他命二甲磺酸盐
• 中文别名: 利右苯丙胺
• 英文名称: lisdexamfetamine
• 英文别名: L-lysine-d-amphetamine；lisdexamphetamine；(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
• CAS: 608137-32-2
• 化学式: C₁₅H₂₅N₃O
• 分子量: 263.383
• InChiKey: VOBHXZCDAVEXEY-JSGCOSHPSA-N

物化性质

• 沸点：
  488.0±45.0 °C(Predicted)
• 密度：
  1.045±0.06 g/cm3(Predicted)
• 物理描述：
  Solid
• 颜色/状态：
  Golden-colored solid from methanol
• 熔点：
  120-122 °C
• 闪点：
  9.7 °C; 49.5 °F (closed cup)
• 溶解度：
  In water, 1500 mg/mL at 25 °C (est)
• 蒸汽压力：
  1.31X10-17 mm Hg at 25 °C (est) (mp 121 °C)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 解离常数：
  pKa1 = 8.43; pKa2 = 10.21; pKa3 = 15.89 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  81.1
• 氢给体数：
  3
• 氢受体数：
  3

ADMET

代谢

利司他明芬他明二甲基磺酸盐（LDX）转化为活性代谢物D-安非他命主要发生在血液中，通过酶切割作用，在LDX从胃肠道腔被主动吸收之后 [A40246]。利司他明芬他明二甲基磺酸盐在血液中被水解为D-安非他命，这是药物产生治疗活性的原因，同时也生成L-赖氨酸。安非他命据报道在苯环的4号位置被氧化形成4-羟基安非他命，或者在侧链的α或β碳上形成α-羟基安非他命或去甲麻黄碱。去甲麻黄碱和4-羟基安非他命都具有活性，并且各自随后被氧化形成4-羟基去甲麻黄碱。α-羟基安非他命经过脱氨过程形成苯乙酮，最终形成苯甲酸及其葡萄糖苷酸和甘氨酸结合物，即马尿酸。尽管参与安非他命代谢的酶尚未被明确鉴定，但已知CYP2D6与从安非他命形成4-羟基安非他命有关 [F2355]。

THe conversion of Lisdexamfetamine dimesylate (LDX) to the active metabolite d-amphetamine occurs primarily in the blood through enzymatic cleavage after active absorption of LDX from the gastrointestinal lumen [A40246]. Lisdexamfetamine dimesylate is hydrolyzed in the blood to d-amphetamine, which is responsible for the drug’s therapeutic activity, as well as L-lysine. Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes the process of deamination to form phenylacetone, which finally forms benzoic acid and its glucuronide and the glycine conjugate, _hippuric acid_. Although the enzymes involved in amphetamine metabolism have not been clearly identified, CYP2D6 is known to be involved with the formation of 4-hydroxy-amphetamine from amphetamine [F2355].

来源:DrugBank

代谢

利司他明芬的代谢途径不同寻常，因为它在被吸收进入血液后，通过红细胞的限速酶促水解代谢，生成右旋安非他命和天然氨基酸L-赖氨酸。

The metabolic route of lisdexamfetamine is unusual because after absorption into the bloodstream it is metabolized by red blood cells to yield d-amphetamine and the natural amino acid, L-lysine, by rate- limited, enzymatic hydrolysis.

来源:Hazardous Substances Data Bank (HSDB)

代谢

利司他明芬被转化为右旋安非他命和L-赖氨酸，这主要发生在血液中，由于红细胞的水解活性。体外数据显示，红细胞对利司他明芬的代谢能力很强；即使在低血细胞比容水平（正常水平的33%）下，也发生了大量水解。利司他明芬不被细胞色素P450酶代谢。

Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这些研究调查了lisdexamfetamine dimesylate (LDX)的吸收和代谢转化，LDX是一种前药兴奋剂，需要转化为d-amphetamine才能发挥作用。在大鼠门静脉和颈静脉血液中评估了LDX的口服吸收，并通过灌注麻醉大鼠的孤立肠段来评估区域性吸收。在表达人肽转运蛋白-1 (PEPT1)的Caco-2细胞和中国仓鼠卵巢(CHO)细胞中研究了LDX的载体介导转运。在大鼠和人体组织匀浆以及人血液组分中研究了LDX的代谢。与全身血液相比，门静脉血液中LDX的含量大约高出10倍。在大鼠小肠灌注后检测到LDX和d-amphetamine，但在结肠中未检测到。LDX在Caco-2细胞中的转运渗透性与头孢氨苄相似，并且在使用PEPT1抑制剂时降低。PEPT1的亲和力也在PEPT1转染的CHO细胞中得到了证明。LDX的代谢主要发生在全血(大鼠和人类)中，仅与红细胞有关。在肝脏和肾脏匀浆中的缓慢水解可能是由于残留血液。完整的LDX通过高容量PEPT1转运蛋白的载体介导吸收，随后在血液中的高容量系统(即红细胞)中代谢为d-amphetamine，这可能是LDX具有一致、可重复的药代动力学特征的原因。

These studies investigated the absorption and metabolic conversion of lisdexamfetamine dimesylate (LDX), a prodrug stimulant that requires conversion to d-amphetamine for activity. Oral absorption of LDX was assessed in rat portal and jugular blood, and perfusion of LDX into isolated intestinal segments of anesthetized rats was used to assess regional absorption. Carrier-mediated transport of LDX was investigated in Caco-2 cells and Chinese hamster ovary (CHO) cells expressing human peptide transporter-1 (PEPT1). LDX metabolism was studied in rat and human tissue homogenates and human blood fractions. LDX was approximately10-fold higher in portal blood versus systemic blood. LDX and d-amphetamine were detected in blood following perfusion of the rat small intestine but not the colon. Transport of LDX in Caco-2 cells had permeability apparently similar to cephalexin and was reduced with concurrent PEPT1 inhibitor. Affinity for PEPT1 was also demonstrated in PEPT1-transfected CHO cells. LDX metabolism occurred primarily in whole blood (rat and human), only with red blood cells. Slow hydrolysis in liver and kidney homogenates was probably due to residual blood. The carrier-mediated absorption of intact LDX, likely by the high-capacity PEPT1 transporter, and subsequent metabolism to d-amphetamine in a high-capacity system in blood (ie, red blood cells) may contribute to the consistent, reproducible pharmacokinetic profile of LDX.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

化合物：赖氨酸苯丙胺

Compound:lisdexamfetamine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：模糊的药物性肝损伤关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：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：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，利他司明（lisdexamfetamine）从胃肠道迅速吸收 [FDA 标签]，[F2355]。**咀嚼片形式：**在健康受试者空腹条件下单次服用60毫克咀嚼片后，利他司明和右旋安非他命的Tmax分别在大约给药后1小时和4.4小时达到 [FDA 标签]。**胶囊形式：**在6至12岁患有ADHD的患儿空腹条件下单次口服（30毫克、50毫克或70毫克）后，利他司明和右旋安非他命的Tmax分别在大约给药后1小时和3.5小时达到 [FDA 标签]。

After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract [FDA label], [F2355]. **Chewable tablet form:** After a single dose of 60 mg a chewable tablet in healthy subjects under fasted conditions, the Tmax of lisdexamfetamine and dextroamphetamine was reached at about 1 hour and 4.4 hour post administration, respectively [FDA label]. **Capsule form:** Following single-dose oral (30 mg, 50 mg, or 70 mg) in patients ages 6 to 12 years with ADHD under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at about 1 hour and 3.5 hours post administration, respectively [FDA label].

来源:DrugBank

吸收、分配和排泄

• 消除途径

在六名健康受试者口服70毫克放射性标记的二甲磺酸赖氨酸安非他命后，约96%的口服剂量放射性在尿液中回收，而在粪便中仅回收了0.3% [FDA标签]，[F2355]。

After the oral administration of a 70mg dose of radiolabeled lisdexamfetamine dimesylate to six healthy subjects, about 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces [FDA label], [F2355].

来源:DrugBank

吸收、分配和排泄

• 分布容积

在健康的成年人中，d-安非他命（通过AUC测量）在稳态下没有积累，连续七天每天一次给药后，也没有lisdexamfetamine dimesylate的积累 [FDA标签]，[F2355]。

There is no accumulation of d-amphetamine (as measured by AUC) at steady state in healthy adults and no accumulation of lisdexamfetamine dimesylate after once-daily dosing for seven consecutive days [FDA label], [F2355].

来源:DrugBank

吸收、分配和排泄

• 清除

在一项针对47名55岁或以上年龄对象的研究中，55-74岁受试者的安非他命清除率大约为0.7升/小时/千克，而75岁或以上受试者的清除率为0.55升/小时/千克。这比年轻人（18-45岁受试者大约为1升/小时/千克）略低[F2355]。

In a study of 47 subjects aged 55 years of age or older, amphetamine clearance was approximately 0.7L/hr/kg for subjects 55-74 years of age and 0.55L/hr/kg for subjects ≥75 years of age. This is slightly reduced compared to younger adults (approximately 1L/hr/kg for subjects 18-45 years of age) [F2355].

来源:DrugBank

吸收、分配和排泄

口服给药后，利他司明迅速从胃肠道吸收。

After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  赖氨酸安非他命二甲磺酸盐 在 硫酸 作用下， 以 乙醇 为溶剂， 生成 lisdexamfetamine sulfate
  参考文献：
  名称：

  [EN] CRYSTALLINE SALTS OF LISDEXAMFETAMINE
  [FR] SELS CRISTALLINS DE LISDEXAMFÉTAMINE

  摘要：

  The present invention relates to pure salts of amphetamine prodrug, in particular, L-lysine-d- amphetamine (known as lisdexamfetamine) and industrial advantageous process for preparation thereof. The present invention relates to the crystalline salts of lisdexamfetamine selected from crystalline lisdexamphetamine dibesylate, crystalline hydrogen sulfate (Form-1 and Form-2). Further, the present invention relates to the preparation of crystalline salts of lisdexamfetamine and wherein salts are selected from dibesylate, hydrogen sulfate and difumarate.

  公开号：

  WO2024003797A1
• 作为产物：
  描述：

  右旋苯丙胺 在 palladium 10% on activated carbon 氢气 作用下， 以 醋酸异丙酯 、 正丁醇 为溶剂， 50.0~97.0 ℃ 、1.03 MPa 条件下， 生成 赖氨酸安非他命二甲磺酸盐
  参考文献：
  名称：

  Methods and Compositions for Preparing Lisdexamfetamine and Salts Thereof

  摘要：

  该发明提供了制备利斯达姆非甲胺及其盐的方法和组合物。更具体地，该发明提供了例如从D-安非他明制备利斯达姆非甲胺的方法。

  公开号：

  US20120157706A1

文献信息

• [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。
• [EN] SUBSTITUTED 2-AZABICYCLO[3.1.1]HEPTANE AND 2-AZABICYCLO[3.2.1]OCTANE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS DE 2-AZABICYCLO[3.1.1]HEPTANE ET DE 2-AZABICYCLO[3.2.1]OCTANE SUBSTITUÉS EN TANT QU'ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：CHRONOS THERAPEUTICS LTD

  公开号：WO2019043407A1

  公开（公告）日：2019-03-07

  There is provided a compound of formula (I), wherein L1 to L3, R1 to R4, X, A and B have meanings given in the description, and pharmaceutically acceptable salts, solvates and prodrugs thereof, which compounds are useful as antagonists of the orexin-1 and orexin-2 receptors or as selective antagonists of the orexin-1 receptor, and thus, in particular, in the treatment or prevention of inter alia substance dependence, addiction, anxiety disorders, panic disorders, binge eating, compulsive disorders, impulse control disorders, cognitive impairment and Alzheimer's disease.

  提供一种化合物，其化学式为（I），其中L1至L3，R1至R4，X，A和B的含义如描述中所给，并且其药学上可接受的盐、溶剂合物和前药，这些化合物可用作促进睡眠素-1和促进睡眠素-2受体的拮抗剂或作为促进睡眠素-1受体的选择性拮抗剂，因此，特别适用于治疗或预防物质依赖、成瘾、焦虑障碍、恐慌障碍、暴饮暴食、强迫障碍、冲动控制障碍、认知障碍和阿尔茨海默病等疾病。
• [EN] TREATMENT OF AUTISM SPECTRUM DISORDERS, OBSESSIVE-COMPULSIVE DISORDER AND ANXIETY DISORDERS<br/>[FR] TRAITEMENT DE TROUBLES DU SPECTRE AUTISTIQUE, DE TROUBLES OBSESSIVO-COMPULSIFS ET DE TROUBLES DE L'ANXIÉTÉ
  申请人：RUGEN HOLDINGS CAYMAN LTD

  公开号：WO2018098128A1

  公开（公告）日：2018-05-31

  Disclosed are methods for treating NMDA receptor-mediated disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. NMDA receptor-mediated disorders include autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders.

  揭示了通过给予特定NR2B亚单位选择性NMDA（N-甲基-D-天冬氨酸）拮抗剂来治疗NMDA受体介导的疾病的方法。NMDA受体介导的疾病包括自闭症谱系障碍、强迫症和焦虑症。
• [EN] TREATMENT OF ANXIETY DISORDERS AND AUTISM SPECTRUM DISORDERS<br/>[FR] TRAITEMENT DES TROUBLES DE L'ANXIÉTÉ ET DES TROUBLES DU SPECTRE AUTISTIQUE
  申请人：RUGEN HOLDINGS CAYMAN LTD

  公开号：WO2016049048A1

  公开（公告）日：2016-03-31

  Disclosed are methods for treating autism spectrum disorders and/or anxiety disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. Anxiety disorders include agoraphobia (with or without panic disorder), generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD).

  本文披露了通过给予特定NR2B亚单位选择性NMDA（N-甲基-D-天冬氨酸）拮抗剂来治疗自闭症谱系障碍和/或焦虑障碍的方法。焦虑障碍包括广场恐惧症（伴有或不伴有惊恐障碍）、广泛性焦虑障碍（GAD）、社交焦虑障碍（SAD）、惊恐障碍（PD）、创伤后应激障碍（PTSD）和强迫症（OCD）。