AMD-070
概述
描述
马维利沙福是一种口服生物利用度高的选择性C-X-C趋化因子受体4 (CXCR4) 拮抗剂。它主要用于治疗疣、低丙种球蛋白血症、感染和髓系造血缺陷综合征 (WHIM) 综合征，这是一种罕见的原发性免疫缺陷疾病。 马维利沙福还在研究其在治疗各种癌症（包括黑色素瘤）和其他慢性中性粒细胞减少症中的潜力 .
科学研究应用
作用机制
马维利沙福通过选择性结合CXCR4受体发挥作用，阻断其天然配体C-X-C趋化因子配体12（也称为基质来源因子-1）的结合。这种抑制阻止了CXCR4信号通路的激活，这些通路参与免疫细胞迁移、造血干细胞归巢和肿瘤进展。 通过调节这些通路，马维利沙福增强了肿瘤微环境中的免疫细胞浸润和激活，从而改善了抗肿瘤反应 .
生化分析
Biochemical Properties
AMD-070 interacts with the CXCR4 chemokine receptor, acting as an antagonist . It binds to the transmembrane regions of the coreceptor, blocking the interaction of the CD4-gp120 complex with the ECL2 domain of the CXCR4 coreceptor .
Cellular Effects
This compound has shown to significantly suppress the anchorage-dependent growth, migration, and matrigel invasion of B88-SDF-1 cells . It also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs .
Molecular Mechanism
The molecular mechanism of this compound involves its binding to the transmembrane regions of the CXCR4 coreceptor, thereby preventing CXCR4-mediated viral entry of T-cell tropic synctium-inducing HIV . This action blocks the interaction of the CD4-gp120 complex with the ECL2 domain of the CXCR4 coreceptor .
Dosage Effects in Animal Models
It has been shown that this compound (2 mg/kg, p.o.) significantly reduces the number of metastatic lung nodules in mice .
Metabolic Pathways
This compound is primarily metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent, CYP2D6 . It is also a substrate of P-glycoprotein (P-gp) .
Transport and Distribution
It is known that this compound is a substrate of P-glycoprotein (P-gp), which plays a role in drug transport .
准备方法
合成路线和反应条件
马维利沙福的合成涉及多个步骤，从市售的起始原料开始 反应条件通常涉及使用有机溶剂、催化剂和控制温度以确保高产率和纯度 .
工业生产方法
马维利沙福的工业生产遵循类似的合成路线，但针对大规模生产进行了优化。 这包括使用连续流动反应器、自动化纯化系统和严格的质量控制措施，以确保一致性和符合监管标准 .
化学反应分析
反应类型
马维利沙福会经历各种化学反应，包括：
氧化： 马维利沙福在特定条件下可以被氧化形成氧化衍生物。
还原： 还原反应可用于修饰喹啉部分。
常用试剂和条件
氧化： 常见的氧化剂包括过氧化氢和高锰酸钾。
还原： 使用硼氢化钠和氢化铝锂等还原剂。
取代： 卤代烷和卤代芳烃等试剂用于取代反应.
主要产物
相似化合物的比较
类似化合物
普乐沙福： 另一种CXCR4拮抗剂，用于治疗非霍奇金淋巴瘤和多发性骨髓瘤患者的干细胞动员。
AMD3100： 一种双环胺分子，也靶向CXCR4受体，并在研究中用于其抗HIV特性.
独特性
马维利沙福的口服生物利用度和对CXCR4受体的选择性是独一无二的。与通过注射给药的普乐沙福和AMD3100不同，马维利沙福可以口服，这使得患者使用起来更加方便。 此外，它对CXCR4的选择性降低了脱靶效应的可能性，从而提高了其安全性 .
属性
IUPAC Name |
N'-(1H-benzimidazol-2-ylmethyl)-N'-[(8S)-5,6,7,8-tetrahydroquinolin-8-yl]butane-1,4-diamine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C21H27N5/c22-12-3-4-14-26(15-20-24-17-9-1-2-10-18(17)25-20)19-11-5-7-16-8-6-13-23-21(16)19/h1-2,6,8-10,13,19H,3-5,7,11-12,14-15,22H2,(H,24,25)/t19-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
WVLHHLRVNDMIAR-IBGZPJMESA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CC(C2=C(C1)C=CC=N2)N(CCCCN)CC3=NC4=CC=CC=C4N3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
C1C[C@@H](C2=C(C1)C=CC=N2)N(CCCCN)CC3=NC4=CC=CC=C4N3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C21H27N5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID60971247 |
Source
|
| Record name | N~1~-[(1H-Benzimidazol-2-yl)methyl]-N~1~-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60971247 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
349.5 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Chemokine receptors expressed on the surface of immune cells are known to play a critical role in virus infection and transmission. CXCR4, and another chemokine receptor CCR5, are involved in HIV infection. The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of only two chemokine receptors, and ends with fusion of viral and cell membranes. Viral entry provides novel therapeutic targets against HIV. To date, at least 3 sub classes of HIV viral entry/fusion inhibitors have emerged: 1. CD4 binding or attachment - targets initial recognition and binding of the viral glycoprotein gp120 to the cell-surface CD4 antigen. 2. Chemokine co-receptor binding - targets binding of virus to the CCR5 or CXCR4 co-receptor. 3. Fusion Inhibition - targets the viral glycoprotein gp41 inhibiting the fusion of virus with the cell. Different strains of HIV prefer one receptor or the other, or may use either receptor to infect cells. * 35% of strains use both CXCR4 and CCR5 * 5% of strains are pure CXCR4 using * 60% of strains are pure CCR5 using * An infected individual may harbor different levels of both CXCR4 and CCR5 using virus * CXCR4 using virus independently predicts CD4 decline and HIV clinical progression and is associated with earlier mortality |
Source
|
| Record name | AMD-070 | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB05501 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
558447-26-0 |
Source
|
| Record name | Mavorixafor [USAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0558447260 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | AMD-070 | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB05501 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | N~1~-[(1H-Benzimidazol-2-yl)methyl]-N~1~-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60971247 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | MAVORIXAFOR | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/0G9LGB5O2W | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Retrosynthesis Analysis
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Feasible Synthetic Routes
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