Maraviroc
Overview
Description
Maraviroc is a chemokine receptor antagonist developed by Pfizer. It is used in combination with other antiretroviral medications to treat CCR5-tropic human immunodeficiency virus type 1 (HIV-1) infection. This compound works by interfering with the interaction between HIV and the CCR5 receptor, thereby preventing the virus from entering human cells .
Preparation Methods
The synthesis of Maraviroc involves several steps. One method includes the “borrowing hydrogen” or “hydrogen autotransfer” method. This process involves the reaction of the tropane triazole with the (S)-amido alcohol, catalyzed by a suitable catalyst . Another method involves the preparation of a tropane derivative by reacting specific compounds under controlled conditions . Industrial production methods focus on optimizing the yield and purity of the final product through improved isolation and purification techniques .
Chemical Reactions Analysis
Maraviroc undergoes various chemical reactions, including substitution and reduction reactions. Common reagents used in these reactions include hydrogen gas and suitable catalysts. The major products formed from these reactions are derivatives of the original compound, which may have different pharmacological properties .
Scientific Research Applications
HIV Treatment
Clinical Efficacy
Maraviroc was first approved for use in patients infected with R5-tropic HIV-1. In pivotal clinical trials such as the MOTIVATE 1 and MOTIVATE 2 studies, this compound demonstrated significant virologic efficacy when combined with optimized background antiretroviral regimens. After 48 weeks, patients treated with this compound showed greater reductions in HIV-1 RNA levels and increases in CD4+ T cell counts compared to placebo groups . Long-term safety evaluations have confirmed that this compound maintains its efficacy and safety profile over extended periods, with no new safety concerns reported through five years of follow-up .
Microbicide Development
Topical Applications
Recent studies have explored the potential of this compound as a topical microbicide to prevent HIV transmission. A notable study demonstrated that a topical gel formulation of this compound provided complete protection against vaginal HIV-1 challenges in humanized mouse models . This finding suggests that this compound could be a promising candidate for future microbicide clinical trials, especially in populations at high risk for HIV infection.
Reactivation of Latent HIV
Latency Reversal Agent
this compound has been investigated for its ability to reactivate latent HIV reservoirs, making it a candidate for use in "shock and kill" strategies aimed at eradicating HIV. In a clinical trial, this compound was shown to disrupt HIV latency in vivo through activation of NF-κB pathways, leading to increased viral expression in latent reservoirs . This application is critical for developing strategies to eliminate hidden viral reservoirs in patients undergoing antiretroviral therapy.
Neuroprotection
Inflammation Reduction
Research has indicated that this compound may exert neuroprotective effects by reducing inflammation associated with central nervous system infections. In vitro studies showed that this compound treatment significantly decreased nitric oxide production in astroglial cell cultures stimulated by pneumococcal bacteria, suggesting a potential role in mitigating neuroinflammation . This application could be relevant for managing neurological complications associated with HIV.
Cardiovascular Health
Impact on Arterial Stiffness
Emerging evidence suggests that this compound may improve cardiovascular health in individuals living with HIV. A study found that this compound treatment was associated with reduced arterial stiffness among patients receiving protease inhibitor-based antiretroviral therapy . This finding highlights the potential cardiovascular benefits of this compound, particularly in populations at risk for cardiovascular diseases due to chronic HIV infection.
Comprehensive Data Table
Mechanism of Action
Maraviroc is an entry inhibitor that works by blocking HIV from entering human cells. Specifically, it is a selective, slowly reversible antagonist of the interaction between the human CCR5 receptor and the HIV-1 gp120 protein . By binding to the CCR5 receptor, this compound prevents the virus from attaching to and entering the host cell, thereby inhibiting viral replication .
Comparison with Similar Compounds
Maraviroc is unique among antiretroviral agents because it targets a host protein, the CCR5 receptor, rather than a viral protein. Similar compounds include other CCR5 antagonists and entry inhibitors. For example, diazabicyclo analogues of this compound have been synthesized and tested for their antiviral activity . These analogues show varying degrees of efficacy in inhibiting HIV-1 entry into host cells. This compound’s specificity for the CCR5 receptor and its ability to block HIV entry make it a valuable addition to the arsenal of antiretroviral drugs .
Biological Activity
Maraviroc (MVC) is a selective antagonist of the CCR5 chemokine receptor, primarily recognized for its role in the treatment of HIV-1 infection. As the first drug in its class approved by the U.S. Food and Drug Administration (FDA), this compound represents a significant advancement in antiretroviral therapy. This article explores the biological activity of this compound, including its mechanism of action, pharmacokinetics, clinical efficacy, and safety profile, supported by data tables and relevant case studies.
This compound functions by blocking the CCR5 receptor on CD4+ T cells, which HIV-1 uses to enter these cells. By preventing the binding of the viral envelope protein gp120 to CCR5, this compound inhibits the fusion of the viral membrane with the host cell membrane, thereby obstructing viral entry.
Key Findings on Mechanism:
- Inhibition Concentration : this compound demonstrated a geometric mean IC90 of 2.0 nM against 43 primary CCR5-tropic HIV-1 isolates .
- Resistance : It remains effective against viruses resistant to other drug classes, showing consistent sensitivity across 200 clinically derived pseudoviruses .
Pharmacokinetics
This compound exhibits favorable pharmacokinetic properties that support its clinical use.
Pharmacokinetic Profile:
| Parameter | Value |
|---|---|
| Oral Bioavailability | Approximately 33% at 300 mg |
| Volume of Distribution | 194 L |
| Protein Binding | ~76% bound to plasma proteins |
| Half-Life | 14-18 hours |
| Metabolism | Primarily via CYP3A |
Coadministration with food can affect absorption; for instance, a high-fat meal reduces Cmax and AUC by approximately 33% .
Clinical Efficacy
This compound has been evaluated in various clinical trials for its efficacy in treating HIV-1. It is particularly beneficial for patients with CCR5-tropic HIV strains.
Case Studies:
- Study on Treatment-Naive Patients : In a randomized controlled trial, this compound combined with other antiretrovirals showed superior virologic response compared to standard therapies in treatment-naive patients.
- Long-Term Efficacy : Longitudinal studies indicate that this compound maintains viral suppression over extended periods without significant resistance development .
Safety Profile
The safety profile of this compound is generally favorable, with no significant cytotoxicity reported in vitro.
Adverse Effects:
While this compound is well-tolerated, some adverse effects include:
Properties
IUPAC Name |
4,4-difluoro-N-[(1S)-3-[(1S,5R)-3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C29H41F2N5O/c1-19(2)27-34-33-20(3)36(27)25-17-23-9-10-24(18-25)35(23)16-13-26(21-7-5-4-6-8-21)32-28(37)22-11-14-29(30,31)15-12-22/h4-8,19,22-26H,9-18H2,1-3H3,(H,32,37)/t23-,24+,25?,26-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
GSNHKUDZZFZSJB-HLMSNRGBSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=NN=C(N1C2CC3CCC(C2)N3CCC(C4=CC=CC=C4)NC(=O)C5CCC(CC5)(F)F)C(C)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC1=NN=C(N1C2C[C@H]3CC[C@@H](C2)N3CC[C@@H](C4=CC=CC=C4)NC(=O)C5CCC(CC5)(F)F)C(C)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C29H41F2N5O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID8048949 |
Source
|
| Record name | Maraviroc | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8048949 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
513.7 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 | Maraviroc | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015584 | |
| 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 |
1.06e-02 g/L |
Source
|
| Record name | Maraviroc | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015584 | |
| 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. | |
Mechanism of Action |
Maraviroc is an entry inhibitor and works by blocking HIV from entering human cells. Specifically maraviroc is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the membrane of CD4 cells (T-cells), preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells., Maraviroc, a synthetic antiretroviral agent, is an HIV entry inhibitor. The drug is a small molecule CCR5 antagonist. HIV enters host cells by attaching to the CD4+ T-cell receptor using 1 of 2 chemokine co-receptors, CCR5 or CXCR4. Maraviroc selectively binds to CCR5 on the cell membrane and prevents the interaction of HIV-1 glycoprotein 120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells. Maraviroc does not inhibit entry of CXCR4-tropic and dual/mixed-tropic HIV-1 into cells. CCR5 is a co-receptor for the most commonly transmitted HIV-1 strains that predominate during the early stages of infection; this form remains the dominant form in many patients with late-stage infection. Maraviroc is active against some strains of HIV-1 resistant to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), HIV protease inhibitors (PIs), and HIV entry and fusion inhibitors (enfuvirtide). HIV-1 strains with reduced susceptibility to maraviroc have been produced in vitro and have emerged during maraviroc therapy., Maraviroc is a member of a therapeutic class called CCR5 co-receptor antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the cell membrane, preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells. CXCR4-tropic and dual-tropic HIV-1 entry is not inhibited by maraviroc., Maraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute peripheral blood leukocyte infection. The mean EC50 value (50% effective concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 ng/mL) in cell culture. ... Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC50 value >10 uM). The antiviral activity of maraviroc against HIV-2 has not been evaluated., Maraviroc (MVC, Celsentri) is an allosteric and reversible inhibitor of the CCR5 chemokine coreceptor. ... MVC exclusively inhibits the replication of R5- tropic HIV-1 variants after binding to the transmembrane CCR5 receptor cavity., For more Mechanism of Action (Complete) data for Maraviroc (6 total), please visit the HSDB record page. |
Source
|
| Record name | Maraviroc | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB04835 | |
| 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 | Maraviroc | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8021 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
White solid from toluene/hexane (2:1), White- to pale-colored powder | |
CAS No. |
376348-65-1, 2414315-81-2 |
Source
|
| Record name | Maraviroc [INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0376348651 | |
| 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 | Maraviroc | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB04835 | |
| 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 | Maraviroc | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8048949 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Maraviroc | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/MD6P741W8A | |
| 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 | Maraviroc, endo- | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/A3C7SRV8DV | |
| 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 | Maraviroc | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8021 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Maraviroc | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015584 | |
| 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. | |
Melting Point |
197-198 °C |
Source
|
| Record name | Maraviroc | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8021 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
