Plerixafor
描述
Plerixafor, sold under the brand name Mozobil, is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients into the bloodstream. These stem cells are then extracted from the blood and transplanted back to the patient. The compound is particularly useful for patients with non-Hodgkin’s lymphoma and multiple myeloma, where it is used in combination with granulocyte-colony stimulating factor to enhance stem cell mobilization .
作用机制
Target of Action
Plerixafor is a small-molecule inhibitor of C-X-C chemokine receptor type 4 (CXCR4) . CXCR4 is a chemokine receptor that plays a crucial role in the trafficking and homing of CD34+ cells to the marrow compartment .
Mode of Action
As an antagonist of CXCR4, this compound blocks the binding of its ligand, stromal cell-derived factor-1-alpha (SDF-1α) . This interaction is vital for the trafficking and homing of CD34+ cells to the marrow compartment. By blocking this interaction, this compound leads to an increase in circulating levels of CD34+ cells .
Biochemical Pathways
The primary biochemical pathway affected by this compound involves the CXCR4/SDF-1α interaction . This interaction is crucial for the trafficking and homing of CD34+ cells to the marrow compartment. By blocking this interaction, this compound disrupts this pathway, leading to an increase in circulating levels of CD34+ cells .
Pharmacokinetics
This compound is quickly absorbed following subcutaneous injection, with peak concentrations reached after 30 to 60 minutes . Up to 58% of the drug is bound to plasma proteins, with the rest residing mostly in extravascular compartments . The drug is excreted via the kidneys .
Result of Action
The primary result of this compound’s action is the mobilization of hematopoietic stem cells (HSCs) to the peripheral blood. This is achieved by blocking the CXCR4/SDF-1α interaction, which increases the circulating levels of CD34+ cells . These stem cells can then be collected and used in autologous stem cell transplantation to replace blood-forming cells destroyed by chemotherapy .
Action Environment
These include older age, a more advanced disease stage, the type of prior chemotherapy, pre-mobilization low platelet count, prior irradiation, or a higher number of prior treatment lines
生化分析
Biochemical Properties
Plerixafor plays a crucial role in biochemical reactions by antagonizing the CXCR4 receptor. This receptor is involved in the trafficking and homing of CD34+ cells to the bone marrow. By blocking the binding of its ligand, stromal cell-derived factor-1-alpha (SDF-1α), this compound increases the levels of circulating CD34+ cells . The compound interacts with three acidic residues in the ligand-binding pocket of CXCR4: Asp171, Asp262, and Glu288 . These interactions are essential for its function as a hematopoietic stem cell mobilizer.
Cellular Effects
This compound has significant effects on various types of cells and cellular processes. It influences cell function by mobilizing hematopoietic stem and progenitor cells from the bone marrow into the peripheral blood . This mobilization is crucial for patients undergoing autologous stem cell transplantation. This compound affects cell signaling pathways by inhibiting the CXCR4 receptor, which plays a role in cell trafficking and homing . Additionally, it impacts gene expression and cellular metabolism by altering the levels of circulating stem cells .
Molecular Mechanism
The molecular mechanism of this compound involves the inhibition of the CXCR4 receptor on CD34+ cells. By blocking the binding of SDF-1α, this compound disrupts the trafficking and homing of hematopoietic stem cells to the bone marrow . This inhibition leads to an increase in the number of circulating stem cells, which can then be collected for transplantation . This compound’s binding interactions with the CXCR4 receptor are reversible, allowing for controlled mobilization of stem cells .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound change over time. The compound is known for its rapid mobilization of hematopoietic stem cells, with blood levels of CD34+ cells peaking between 6 and 9 hours after administration . This compound is stable and does not undergo significant degradation, ensuring its effectiveness over the duration
准备方法
Synthetic Routes and Reaction Conditions: Plerixafor is synthesized through a multi-step process involving the reaction of 1,4,8,11-tetraazacyclotetradecane with paratoluensulfonyl chloride, followed by segmental crystallization and purification. The intermediate product undergoes a bridging reaction with alpha,alpha’-dibromopxylene in anhydrous acetonitrile under the action of an acid-binding agent. Finally, deprotection in a mixed acid yields crude this compound, which is then refined to obtain the target product .
Industrial Production Methods: The industrial production of this compound involves similar synthetic routes but is optimized for higher yield and purity. Segmental crystallization is employed to effectively remove impurities, resulting in a product with purity higher than 99.5% and single impurity content less than 0.1% .
化学反应分析
Types of Reactions: Plerixafor primarily undergoes substitution reactions due to its polyamine structure. The compound can form complexes with metal ions such as nickel and copper, which have been studied for their electrochemical properties .
Common Reagents and Conditions:
Substitution Reactions: Involve reagents like paratoluensulfonyl chloride and alpha,alpha’-dibromopxylene.
Complex Formation: Involves metal ions like nickel and copper under specific electrochemical conditions.
Major Products:
Substitution Reactions: Yield intermediates that are further processed to obtain this compound.
Complex Formation: Results in dinickel(II) and dicopper(II) complexes.
科学研究应用
Plerixafor has a wide range of applications in scientific research:
相似化合物的比较
Motixafortide: Another CXCR4 antagonist used for stem cell mobilization.
Generic Plerixafor (Pleksor): A generic version of this compound with similar efficacy and safety profiles.
Comparison:
This compound vs. Motixafortide: Both compounds are used for stem cell mobilization, but motixafortide has shown higher mobilization rates in clinical trials.
This compound vs. Generic this compound: Studies have shown that generic this compound (Pleksor) produces similar cumulative collection yields with fewer doses and collection days compared to the brand-name this compound (Mozobil).
This compound’s unique ability to effectively mobilize hematopoietic stem cells, combined with its well-established safety profile, makes it a valuable tool in the treatment of hematological malignancies.
属性
IUPAC Name |
1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C28H54N8/c1-9-29-15-17-31-13-3-21-35(23-19-33-11-1)25-27-5-7-28(8-6-27)26-36-22-4-14-32-18-16-30-10-2-12-34-20-24-36/h5-8,29-34H,1-4,9-26H2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
YIQPUIGJQJDJOS-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CNCCNCCCN(CCNC1)CC2=CC=C(C=C2)CN3CCCNCCNCCCNCC3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C28H54N8 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID70869520 |
Source
|
| Record name | Plerixafor | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID70869520 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
502.8 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Plerixafor | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015681 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Soluble |
Source
|
| Record name | Plerixafor | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06809 | |
| 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) | |
Mechanism of Action |
Plerixafor inhibits the CXCR4 chemokine receptors on CD34+ cells and reversibly blocks binding of the ligand, stromal cell-derived factor-1-alpha (SDF-1α). By blocking the interaction between SDF-1α and CXCR4 with plerixafor, mobilization of progenitor cells is triggered. Filgrastim, a granulocyte-colony stimulating factor, is added to enhance CD34+ cell mobilization, thus increasing the yield of stem cells- an important determinant of graft adequacy. |
Source
|
| Record name | Plerixafor | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06809 | |
| 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. |
110078-46-1 |
Source
|
| Record name | Plerixafor | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=110078-46-1 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Plerixafor [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0110078461 | |
| 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 | Plerixafor | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06809 | |
| 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 | Plerixafor | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID70869520 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Plerixafor | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | PLERIXAFOR | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/S915P5499N | |
| 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. | |
| Record name | Plerixafor | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015681 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
A: Plerixafor acts as a reversible antagonist of the CXCR4 chemokine receptor, specifically targeting the interaction between CXCR4 and its ligand, stromal cell-derived factor 1 (SDF-1) ,. This interaction typically retains hematopoietic stem cells (HSCs) within the bone marrow microenvironment. By blocking this interaction, this compound promotes the release of HSCs into the peripheral blood, facilitating their collection for transplantation ,.
ANone: this compound, also known as AMD3100, has the molecular formula C50H74F12N10O2 and a molecular weight of 1123.2 g/mol. Spectroscopic data, including NMR and mass spectrometry, can be found in the literature and manufacturer's documentation.
ANone: While specific studies on material compatibility are limited, this compound is typically formulated for subcutaneous injection. Research suggests that it remains stable under standard storage conditions. Further investigations on compatibility with specific materials or under diverse conditions might be needed for novel applications.
A: Studies have shown that prior treatment with granulocyte colony-stimulating factor (G-CSF) can enhance the mobilization of primitive hematopoietic cells by this compound in healthy donors . This suggests a synergistic effect and highlights the importance of mobilization strategy sequencing for optimal results.
A: Research suggests that selectively administering this compound to patients with a high risk of poor mobilization, identified by factors like low blood CD34+ cell counts or previous treatment history, can effectively enhance stem cell collection without significantly increasing overall costs . This approach maximizes resource utilization and potentially improves patient outcomes.
A: Several studies have explored different algorithms for this compound administration based on factors like peripheral CD34+ cell counts, previous treatment history, and risk factors for poor mobilization ,,. These algorithms aim to personalize treatment, optimize stem cell yields, and potentially reduce unnecessary healthcare costs.
A: While primarily used as a salvage therapy for poor mobilizers, studies have investigated the efficacy of this compound as a primary mobilization agent, particularly in high-risk patients. Some research suggests that a risk-based algorithm for this compound use can lead to successful mobilization in a single apheresis session , potentially reducing the need for multiple procedures.
A: Research on this compound administration at different times, such as 5:00 PM instead of the conventional 10:00 PM, suggests similar efficacy and safety profiles . This flexibility allows for greater patient convenience and ensures compliance without compromising safety.
ANone: Long-term safety data on this compound are limited due to its relatively recent introduction and the nature of its use in a specific patient population. Ongoing research and post-marketing surveillance are crucial to assess potential long-term effects, particularly in those undergoing transplantation who may require extended follow-up.
A: Studies suggest that while this compound effectively mobilizes HSCs, the collected stem cell products may have lower numbers of colony-forming units (CFUs) per CD34+ cell compared to those mobilized with G-CSF alone . This finding raises questions about potential differences in the long-term repopulating capacity of these cells and warrants further investigation.
A: Research indicates that this compound can mobilize various cell populations in addition to HSCs, including myeloid-derived suppressor cells (MDSCs) . Interestingly, grafts enriched with MDSCs have been associated with potential benefits, such as a lower incidence of graft-versus-host disease (GvHD) in preclinical models.
A: Given its mechanism of action, researchers are exploring the potential use of this compound in other areas, such as enhancing the delivery of anti-cancer drugs to tumors that express CXCR4 and promoting tissue regeneration by influencing stem cell trafficking. Further preclinical and clinical studies are needed to validate these applications.
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