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| Targets |
Nifeviroc targets the CCR5 (C-C chemokine receptor type 5) receptor, a G protein-coupled receptor (GPCR) expressed on the surface of immune cells, including T cells, macrophages, and dendritic cells. CCR5 serves as a co-receptor for HIV-1 entry into host cells, along with the CD4 receptor. The HIV-1 envelope glycoprotein gp120 binds to CD4 and then to CCR5, triggering a conformational change that allows viral fusion and entry into the cell. Nifeviroc acts as a selective antagonist at CCR5, blocking the interaction between HIV-1 gp120 and CCR5 and preventing viral entry. The compound is selective for CCR5 over other chemokine receptors, reducing the risk of off-target effects. By blocking CCR5, Nifeviroc inhibits HIV-1 replication and may also modulate inflammatory responses mediated by CCR5 signaling.
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| ln Vitro |
In vitro, Nifeviroc inhibits HIV-1 entry into CCR5-expressing cells by blocking the interaction between HIV-1 gp120 and the CCR5 receptor. In cell-based assays using CCR5-expressing cell lines (e.g., U87-CD4-CCR5 cells or PBMCs infected with HIV-1), treatment with Nifeviroc at concentrations ranging from 0.1 nM to 10 μM results in inhibition of viral replication, as measured by p24 antigen production or viral RNA levels. The compound's antiviral activity is concentration-dependent, with IC₅₀ values typically in the low nanomolar range. Nifeviroc also inhibits CCR5-mediated chemotaxis in response to the natural CCR5 ligands CCL3, CCL4, and CCL5 (RANTES). The compound's selectivity for CCR5 over other chemokine receptors (e.g., CXCR4) has been confirmed in receptor binding and functional assays. These in vitro findings support Nifeviroc's potential as an HIV entry inhibitor.
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| ln Vivo |
In vivo, Nifeviroc has been evaluated in preclinical and clinical studies for the treatment of HIV-1 infection. The compound is orally active and has demonstrated antiviral efficacy in animal models of HIV infection. In clinical studies, Nifeviroc has been investigated as a potential treatment for HIV-1 infection in patients with CCR5-tropic virus. The compound's oral bioavailability and favorable pharmacokinetic profile support its use as an investigational therapeutic agent. Nifeviroc may also have applications in investigating inflammatory responses to HIV-1 infection and other CCR5-mediated inflammatory conditions. However, specific clinical efficacy data are not fully detailed in the public literature. The compound is an investigational drug and has not received FDA approval.
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| Enzyme Assay |
In vitro receptor binding assays for Nifeviroc typically involve competition binding studies using radiolabeled CCR5 ligands. A typical protocol: membrane preparations from CCR5-expressing cells (e.g., CHO-CCR5 or HEK293-CCR5) are incubated with [¹²⁵I]-CCL5/RANTES (20-50 pM) and varying concentrations of Nifeviroc (0.01 nM to 10 μM) in binding buffer (50 mM HEPES, pH 7.4, 5 mM MgCl₂, 0.1% BSA, 0.1 mM bacitracin) for 60-90 minutes at room temperature. Non-specific binding is determined in the presence of 1 μM unlabeled CCL5. Bound radioactivity is separated by rapid filtration through glass fiber filters and quantified by scintillation counting. IC₅₀ and Kᵢ values are calculated from competition curves using nonlinear regression. For selectivity assays, binding to other chemokine receptors (e.g., CXCR4, CCR2, CCR3) is assessed using similar protocols. Each concentration is tested in triplicate, and experiments are repeated at least three times.
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| Cell Assay |
In vitro cell-based assays for Nifeviroc are performed using CCR5-expressing cell lines and HIV-1 infection models. A typical protocol for HIV-1 inhibition: U87-CD4-CCR5 cells or PBMCs are seeded in 96-well plates at 50,000-100,000 cells/well. Cells are pre-incubated with Nifeviroc at concentrations ranging from 0.1 nM to 10 μM for 1 hour. Cells are then infected with HIV-1 (CCR5-tropic strain such as HIV-1 BaL) at an MOI of 0.01-0.1. After 3-7 days of culture, viral replication is measured by p24 antigen ELISA or by measuring viral RNA in the supernatant. Antiviral activity is expressed as the percent inhibition of p24 production compared to vehicle controls. For chemotaxis assays, CCR5-expressing cells are placed in the upper chamber of a Transwell plate, and Nifeviroc is added to both chambers. CCL5/RANTES (10-100 nM) is added to the lower chamber as a chemoattractant. After 2-4 hours, migrated cells are counted. Each condition is tested in triplicate, and experiments are repeated at least three times.
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| Animal Protocol |
In vivo animal studies for Nifeviroc have been conducted in rodent models of HIV infection or inflammation. A typical protocol: immunodeficient mice (e.g., NSG or hu-PBL-SCID mice) engrafted with human PBMCs are infected with HIV-1 (CCR5-tropic strain). Nifeviroc is administered via oral gavage at doses of 1-30 mg/kg, daily or twice daily, for 2-4 weeks. Viral load is measured in plasma by qRT-PCR at regular intervals. CD4+ T cell counts are monitored by flow cytometry. For inflammation studies, Nifeviroc may be administered to mice with CCR5-mediated inflammatory conditions, and inflammatory markers are measured. Efficacy is assessed by comparing viral load and CD4+ cell counts between treatment and vehicle control groups. The compound's oral bioavailability and in vivo activity have been demonstrated in preclinical studies.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Nifeviroc have been evaluated in preclinical and clinical studies. The compound is orally active and has demonstrated oral bioavailability. Following oral administration, Nifeviroc is absorbed and reaches therapeutic concentrations in the systemic circulation. The compound's half-life, volume of distribution, clearance, and protein binding have been evaluated in preclinical models and in clinical studies. Nifeviroc is metabolized in the liver, likely via CYP450 enzymes, and its metabolites are eliminated via the renal and biliary routes. The compound's pharmacokinetic profile supports once-daily or twice-daily dosing in clinical studies. Specific pharmacokinetic parameters (e.g., Cmax, Tmax, AUC, t₁/₂) have been reported in clinical trial publications. The compound is stable under recommended storage conditions.
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| Toxicity/Toxicokinetics |
Nifeviroc is an investigational drug that has been studied in clinical trials for the treatment of HIV-1 infection. In preclinical and clinical studies, the compound has been generally well-tolerated at therapeutic doses. Common adverse effects may include gastrointestinal disturbances and headache. The compound has not been associated with significant organ toxicity in preclinical studies. However, formal toxicology data are proprietary and not fully disclosed in public literature. Standard laboratory safety precautions should be followed when handling Nifeviroc: use of personal protective equipment (gloves, safety goggles, lab coat) and handling in a well-ventilated fume hood. The compound should be stored as recommended by the manufacturer. Researchers should consult the safety data sheet (SDS) before handling.
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| References | |
| Additional Infomation |
Structure in the first source
Additional information for Nifeviroc: The compound has a CAS number of 934740-33-7. Its molecular formula is C₃₃H₄₂N₄O₆ and molecular weight is 590.71 g/mol. Synonyms include TD-0232. The compound is a potent CCR5 receptor antagonist. It is an orally active CCR5 antagonist for the treatment of HIV-1 infection. Purity is typically ≥97%. The compound is an investigational drug and has not received FDA approval for clinical use. It is for research use only and is not approved for clinical applications outside of investigational studies. |
| Molecular Formula |
C33H42N4O6
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|---|---|
| Molecular Weight |
590.72
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| Exact Mass |
590.31
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| Elemental Analysis |
C, 67.10; H, 7.17; N, 9.48; O, 16.25
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| CAS # |
934740-33-7
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| Related CAS # |
934740-33-7;
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| PubChem CID |
16663418
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
761.1±60.0 °C at 760 mmHg
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| Flash Point |
414.1±32.9 °C
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| Vapour Pressure |
0.0±2.7 mmHg at 25°C
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| Index of Refraction |
1.631
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| LogP |
5.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
43
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| Complexity |
961
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O[C@@]1(CN(C(C2CCCC2)=O)C[C@@H]1CN1CCC(N(CC=C)C(=O)OCC2C=CC([N+](=O)[O-])=CC=2)CC1)C1C=CC=CC=1
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| InChi Key |
JNSKQYZFEVKYDB-UVMMSNCQSA-N
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| InChi Code |
InChI=1S/C33H42N4O6/c1-2-18-36(32(39)43-23-25-12-14-30(15-13-25)37(41)42)29-16-19-34(20-17-29)21-28-22-35(31(38)26-8-6-7-9-26)24-33(28,40)27-10-4-3-5-11-27/h2-5,10-15,26,28-29,40H,1,6-9,16-24H2/t28-,33-/m0/s1
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| Chemical Name |
(4-nitrophenyl)methyl N-[1-[[(3S,4R)-1-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl]methyl]piperidin-4-yl]-N-prop-2-enylcarbamate
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| Synonyms |
TD 0232 TD0232 TD-0232
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~95 mg/mL (~160.82 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6928 mL | 8.4642 mL | 16.9285 mL | |
| 5 mM | 0.3386 mL | 1.6928 mL | 3.3857 mL | |
| 10 mM | 0.1693 mL | 0.8464 mL | 1.6928 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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