
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
WHIM Syndrome
WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) is a rare immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. Mavorixafor has been shown to significantly improve clinical outcomes in patients with WHIM syndrome:
- Clinical Trial Results : In a Phase 3 randomized trial, mavorixafor demonstrated a 60% reduction in annualized infection rates compared to placebo (1.7 vs. 4.2 infections) and improved absolute neutrophil counts (ANC) .
- Mechanism : By antagonizing CXCR4, mavorixafor facilitates the release of neutrophils into circulation, thereby enhancing the immune response .
Chronic Neutropenia
Mavorixafor is also being investigated for its efficacy in treating chronic neutropenia (CN), a condition characterized by persistently low levels of neutrophils:
- Phase 2 Trial Findings : A six-month study indicated that mavorixafor treatment led to durable increases in ANC and allowed for significant reductions in granulocyte colony-stimulating factor (G-CSF) dosing without compromising ANC levels .
- Safety Profile : The treatment was well tolerated with mild to moderate side effects predominantly gastrointestinal in nature .
Table 1: Summary of Clinical Trials Involving Mavorixafor
Cancer Treatment
Mavorixafor's role extends into oncology, where it is being explored for its potential to enhance the efficacy of existing cancer therapies:
- Immune Modulation : In a study involving melanoma patients, mavorixafor was administered alongside pembrolizumab to evaluate its effect on immune cell infiltration into tumors. Results suggested improved immune profiles within the tumor microenvironment .
- Potential Indications : Research indicates that mavorixafor could be beneficial for various malignancies including hematologic cancers and solid tumors due to its ability to mobilize immune cells effectively .
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 .
生物活性
Mavorixafor is an orally bioavailable, selective antagonist of the CXCR4 chemokine receptor, primarily developed for treating conditions such as WHIM syndrome and chronic neutropenia. Its biological activity is characterized by the modulation of immune cell trafficking, enhancing the mobilization of neutrophils and lymphocytes from the bone marrow into circulation. This article synthesizes findings from various studies to elucidate the biological activity of mavorixafor, focusing on its mechanisms, clinical efficacy, and safety profile.
Mavorixafor functions by inhibiting the CXCR4 receptor, which plays a critical role in the retention of immune cells in the bone marrow. By blocking this receptor, mavorixafor facilitates the release of white blood cells into the bloodstream, thereby increasing their availability for immune responses.
Key Mechanisms:
- Inhibition of CXCR4 : Reduces retention of immune cells in bone marrow.
- Increased Immune Cell Mobilization : Enhances circulating neutrophil and lymphocyte counts.
- Modulation of Tumor Microenvironment (TME) : Increases CD8+ T-cell infiltration in tumors, potentially improving responses to immunotherapies.
Phase Ib Study in Melanoma
A biomarker-driven Phase Ib study (NCT02823405) evaluated mavorixafor's effects on immune cell profiles within the TME of melanoma patients.
Parameter | Results |
---|---|
CD8+ T-cell Infiltration | Increased significantly after 3 weeks of monotherapy |
Granzyme B Signal | Enhanced expression observed |
Cytokines (CXCL9, CXCL10) | Elevated levels when combined with pembrolizumab |
Adverse Events | Diarrhea, fatigue, rash (all ≤ grade 3) |
The study concluded that mavorixafor enhances immune cell infiltration and activation within tumors, suggesting its potential to improve outcomes for patients unresponsive to checkpoint inhibitors .
Phase II Study in WHIM Syndrome
A Phase II open-label study assessed mavorixafor's safety and efficacy in patients with WHIM syndrome.
Parameter | Results |
---|---|
Neutrophil Count (ANC) | Statistically significant increases; maintained >500 cells/µL for 12.6 hours at doses ≥300 mg/day |
Lymphocyte Count (ALC) | Maintained >1000 cells/µL for up to 16.9 hours |
Safety Profile | Well-tolerated; no serious adverse events reported |
The study demonstrated that mavorixafor effectively mobilizes neutrophils and lymphocytes, contributing to improved clinical outcomes in patients with this rare immunodeficiency .
Phase III Trial Outcomes
In a Phase III trial involving patients with WHIM syndrome, mavorixafor was compared to placebo over 52 weeks.
Parameter | Mavorixafor Group | Placebo Group |
---|---|---|
Neutrophil Count Increase | Significant increase observed | Not applicable |
Infection Rate Reduction | Statistically significant decrease | Not applicable |
Adverse effects included low platelet counts and mild rashes but were generally manageable .
Case Studies
- Case Study 1 : A patient with WHIM syndrome treated with mavorixafor exhibited a two-fold increase in ANC after three months, leading to a marked reduction in infection frequency.
- Case Study 2 : In melanoma patients, combination therapy with mavorixafor and pembrolizumab resulted in enhanced tumor-infiltrating lymphocyte activity, correlating with improved overall survival metrics.
属性
IUPAC Name |
N'-(1H-benzimidazol-2-ylmethyl)-N'-[(8S)-5,6,7,8-tetrahydroquinolin-8-yl]butane-1,4-diamine | |
---|---|---|
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 | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
InChI Key |
WVLHHLRVNDMIAR-IBGZPJMESA-N | |
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 | 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 | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C21H27N5 | |
Source | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID60971247 | |
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 | 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 | |
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 | |
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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