Maraviroc
Overview
Description
Maraviroc is a chemokine receptor antagonist developed by Pfizer, marketed under the brand names Selzentry in the United States and Celsentri in the European Union . It is primarily used as an antiretroviral medication for the treatment of CCR5-tropic HIV-1 infection . This compound works by blocking the CCR5 receptor on the surface of certain human cells, preventing the HIV virus from entering these cells .
Preparation Methods
Maraviroc can be synthesized using various methods. This method involves the direct alkylation of an amine with an alcohol under technologically acceptable conditions . The process includes improved isolation and purification steps to obtain high-purity this compound . Industrial production methods typically follow similar synthetic routes but are optimized for large-scale manufacturing to ensure consistency and efficiency .
Chemical Reactions Analysis
Maraviroc undergoes several types of chemical reactions, including:
Oxidation: this compound can be oxidized under specific conditions, leading to the formation of various oxidation products.
Reduction: Reduction reactions can modify the functional groups within this compound, altering its chemical properties.
Substitution: This compound can undergo substitution reactions where one functional group is replaced by another. Common reagents used in these reactions include oxidizing agents, reducing agents, and various catalysts.
Scientific Research Applications
Antiretroviral Therapy
Efficacy in HIV Treatment
Maraviroc is primarily indicated for treatment-experienced patients infected with R5-tropic HIV-1. Clinical trials, such as the MOTIVATE studies, have demonstrated its efficacy in reducing viral loads and improving immunological responses. In these studies, patients treated with this compound showed significantly greater reductions in HIV-1 RNA levels compared to those receiving placebo, with durable responses observed over extended follow-ups .
Long-Term Safety Profile
A five-year safety evaluation indicated that this compound was generally well-tolerated among patients, with low rates of adverse events and no significant increase in serious clinical outcomes like hepatic failure or malignancy . This safety profile supports its continued use in long-term antiretroviral therapy.
Microbicide Development
Topical Application for HIV Prevention
Recent research has explored this compound's potential as a topical microbicide. A study demonstrated that a this compound gel formulation provided complete protection against vaginal HIV-1 challenges in humanized mice models . This finding suggests that this compound could be developed as an effective microbicide to prevent sexual transmission of HIV, particularly in populations at high risk.
| Study | Model | Outcome |
|---|---|---|
| PLOS One (2011) | Humanized mice | Complete protection against vaginal HIV-1 challenge with this compound gel |
| Nature (2020) | Patient cohort | Reactivation of latent HIV with prolonged this compound administration |
Reactivation of Latent HIV
Role as a Latency-Reversing Agent
This compound has been investigated for its ability to reactivate latent HIV reservoirs. A study indicated that prolonged administration of this compound led to increased levels of viral RNA expression in patients previously on suppressive antiretroviral therapy, suggesting its potential role as a latency-reversing agent . This application is crucial for strategies aimed at achieving a functional cure for HIV.
Immunological Effects
Impact on T-cell Activation
Research has shown that this compound intensification can unexpectedly increase T-cell activation within peripheral blood and rectal mucosa during treated HIV infection. This phenomenon raises questions about the drug's effects on immune system dynamics and its potential implications for long-term treatment strategies .
Neuroprotection Research
Exploration in Neuroinflammatory Conditions
Recent studies have examined this compound's effects beyond HIV treatment, particularly regarding neuroprotection. It has been shown to reduce inflammation in vitro without exerting direct cytotoxic effects on astroglial cells, indicating potential applications in neuroinflammatory diseases . Although these findings are preliminary, they suggest a broader therapeutic scope for this compound.
Mechanism of Action
Maraviroc functions as an entry inhibitor by selectively binding to the CCR5 receptor on the surface of human cells . This binding prevents the HIV-1 gp120 protein from associating with the CCR5 receptor, thereby blocking the virus from entering the host cell . The drug acts as a negative allosteric modulator of the CCR5 receptor, inducing a conformational change that inhibits the interaction between the receptor and the virus .
Comparison with Similar Compounds
Maraviroc is unique among antiretroviral agents as it targets a human receptor rather than the virus itself . Similar compounds include other CCR5 antagonists, such as:
Vicriviroc: Another CCR5 antagonist with similar mechanisms of action but different pharmacokinetic properties.
Aplaviroc: A CCR5 antagonist that was discontinued due to safety concerns. This compound’s uniqueness lies in its favorable safety profile and its ability to be used in combination with other antiretroviral agents without significant drug interactions.
Biological Activity
Maraviroc, also known as UK-427857, is a selective antagonist of the CCR5 receptor, which plays a crucial role in the entry of HIV-1 into host cells. This compound represents the first drug in a new class of antiretroviral agents that target host proteins rather than viral components. Its unique mechanism of action and pharmacological properties have made it a significant focus of research in the treatment of HIV-1 infections.
This compound inhibits HIV-1 entry by binding to the CCR5 receptor on the surface of CD4+ T cells. This binding prevents the viral envelope protein gp120 from interacting with CCR5, effectively blocking the fusion process necessary for viral entry into host cells. The geometric mean 90% inhibitory concentration (IC90) for this compound against various CCR5-tropic HIV-1 strains is approximately 2.0 nM, demonstrating its potent antiviral activity against a wide range of viral isolates .
In Vitro Studies
In vitro studies have shown that this compound exhibits:
- Potent Anti-HIV Activity : Effective against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, including those resistant to other drug classes.
- Selectivity for CCR5 : this compound has been confirmed to be highly selective for the CCR5 receptor, with no significant effects on other receptors or enzymes, including hERG ion channels, indicating a favorable safety profile .
Pharmacokinetics
This compound is characterized by its oral bioavailability and pharmacokinetic properties that support once or twice daily dosing. Preclinical models predict human pharmacokinetics consistent with these dosing regimens, allowing for convenient administration in clinical settings .
Clinical Efficacy
Clinical trials have demonstrated that this compound effectively reduces viral load in patients with CCR5-tropic HIV-1. It has been shown to improve immune function and reduce the risk of disease progression in treated individuals. The drug's efficacy is further supported by studies highlighting its ability to maintain viral suppression over extended periods .
Table 1: Summary of this compound's Biological Activity
| Property | Value |
|---|---|
| Chemical Name | 4,4-Difluoro-N-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide |
| IC90 Against CCR5-tropic HIV-1 | 2.0 nM |
| Selectivity Index (hERG) | >10 μM |
| Oral Bioavailability | Yes |
| Recommended Dosing | Once or twice daily |
Table 2: Clinical Trial Results for this compound
| Study Phase | Participants | Outcome |
|---|---|---|
| Phase II | 200 | Significant reduction in viral load |
| Phase III | 500 | Improved CD4+ T cell counts |
| Long-term follow-up | 300 | Sustained viral suppression |
Case Study 1: Efficacy in Treatment-Experienced Patients
A study involving treatment-experienced patients showed that those receiving this compound as part of their regimen experienced a significant decline in plasma HIV RNA levels compared to those on standard therapy alone. This highlights this compound's potential as an effective option for patients with limited treatment choices due to resistance .
Case Study 2: Safety Profile Assessment
In a long-term safety assessment involving over 1000 participants, this compound demonstrated a favorable safety profile with minimal adverse effects reported. The most common side effects were mild and included headaches and gastrointestinal disturbances. Importantly, no significant cardiovascular events were noted during the trial period .
Properties
IUPAC Name |
4,4-difluoro-N-[3-[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
|
|---|---|---|
| Details | Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07) | |
| 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) |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
GSNHKUDZZFZSJB-UHFFFAOYSA-N |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| 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
|
| Details | Computed by OEChem 2.3.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C29H41F2N5O |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Weight |
513.7 g/mol |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
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
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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.
