Vicriviroc

Voies de synthèse et conditions réactionnelles

La synthèse du vicriviroc implique plusieurs étapes, à commencer par la préparation d'intermédiaires clésLes conditions de réaction spécifiques, telles que la température, les solvants et les catalyseurs, sont optimisées pour garantir un rendement élevé et une pureté élevée .

Méthodes de production industrielle

La production industrielle du this compound suit des voies de synthèse similaires, mais est mise à l'échelle pour répondre aux demandes commerciales. Le processus implique des mesures strictes de contrôle de la qualité pour garantir la cohérence et la conformité aux normes réglementaires. Des techniques de pointe, telles que la chimie en flux continu et la synthèse automatisée, peuvent être utilisées pour améliorer l'efficacité et réduire les coûts de production .

Types de réactions

Le vicriviroc subit diverses réactions chimiques, notamment :

Oxydation : Le this compound peut être oxydé pour former du this compound N-oxyde, un métabolite majeur.

Réduction : Les réactions de réduction peuvent être utilisées pour modifier des groupes fonctionnels spécifiques au sein de la molécule.

Substitution : Les réactions de substitution peuvent être utilisées pour introduire ou remplacer des substituants sur le noyau pyrimidine.

Réactifs et conditions courants

Les réactifs courants utilisés dans ces réactions comprennent des agents oxydants comme les enzymes du cytochrome P450 pour l'oxydation, des agents réducteurs pour la réduction et des nucléophiles pour les réactions de substitution. Les conditions de réaction telles que la température, le pH et le choix du solvant sont soigneusement contrôlées pour obtenir les résultats souhaités .

Principaux produits formés

Les principaux produits formés à partir de ces réactions comprennent le this compound N-oxyde et d'autres métabolites qui résultent de la modification du composé parent .

Applications de recherche scientifique

Chimie : Le this compound sert de composé modèle pour étudier les inhibiteurs du CCR5 et leurs interactions avec le VIH-1.

Biologie : La recherche sur le this compound a fourni des informations sur les mécanismes d'entrée virale et le rôle du CCR5 dans l'infection à VIH-1.

Médecine : Le this compound a été étudié dans des essais cliniques pour son efficacité dans le traitement des infections à VIH-1, en particulier chez les patients ayant reçu un traitement antérieur.

Industrie : Le développement et la production du this compound ont contribué aux progrès de la fabrication pharmaceutique et du contrôle de la qualité.

Mécanisme d'action

Le this compound agit comme un antagoniste allostérique non compétitif du récepteur CCR5. Il se lie à une poche hydrophobe entre les hélices transmembranaires près de la surface extracellulaire du récepteur CCR5. Cette liaison provoque un changement conformationnel dans le récepteur, empêchant la liaison de la protéine gp120 du VIH-1 au CCR5. En conséquence, l'entrée du VIH-1 dans les cellules hôtes est inhibée, bloquant les étapes initiales du cycle de vie viral .

Phase 2 Study (ACTG A5211)

• Objective : To assess the safety and virologic activity of vicriviroc in treatment-experienced subjects.
• Design : Double-blind, randomized trial involving 118 subjects who received either this compound (5 mg, 10 mg, or 15 mg) or placebo over 24 weeks.
• Results :
  • Significant reductions in HIV-1 RNA levels were observed in all this compound groups compared to placebo.
  • The mean change in HIV-1 RNA at week 24 was greater for this compound groups (−1.51 to −1.86 log copies/mL) compared to placebo (+0.06 log copies/mL) with statistical significance ($P<.01$) .
  • Virologic failure rates were lower in the this compound groups, with time to failure significantly longer for those receiving this compound compared to placebo .

VICTOR-E1 Study

• Objective : To evaluate the molecular basis for resistance mutations in subjects treated with this compound.
• Findings : Among 79 this compound-treated subjects, a subset developed resistance mutations leading to virologic failure. Genetic analysis revealed specific amino acid changes in the viral envelope that were associated with reduced susceptibility to this compound .

Efficacy and Safety Profile

This compound has demonstrated a favorable safety profile across multiple studies. Adverse events were comparable between this compound and placebo groups, with no significant increase in severe adverse events reported . Long-term follow-up indicated sustained virologic suppression in approximately 49% of subjects who achieved viral load suppression below 50 copies/mL after three years .

Resistance Patterns

Resistance to this compound has been documented, primarily among treatment-experienced patients. Studies indicate that while some patients develop resistance mutations, only a small proportion of treatment failures were directly associated with these mutations . The mapping of resistance mutations has revealed diverse genetic alterations that contribute to reduced drug efficacy .

Data Summary Table

Conclusions

This compound represents a promising therapeutic option for HIV-1-infected individuals who are treatment-experienced. Its ability to suppress viral load effectively while maintaining a manageable safety profile underscores its potential role in antiretroviral therapy. However, ongoing research is necessary to further elucidate its resistance patterns and optimize its use within combination therapy regimens.

Vicriviroc functions as a noncompetitive allosteric antagonist of the CCR5 receptor. It binds to a hydrophobic pocket between the transmembrane helices near the extracellular surface of the CCR5 receptor. This binding causes a conformational change in the receptor, preventing the binding of the HIV-1 gp120 protein to CCR5. As a result, the entry of HIV-1 into host cells is inhibited, blocking the initial stages of the viral life cycle .

Le vicriviroc fait partie d'une classe de composés appelés inhibiteurs du CCR5. Des composés similaires comprennent :

Maraviroc : Un autre inhibiteur du CCR5 approuvé pour une utilisation clinique dans le traitement des infections à VIH-1.

Aplaviroc : Un inhibiteur du CCR5 qui a été abandonné en raison de préoccupations concernant l'hépatotoxicité.

INCB009471 : Un inhibiteur du CCR5 en développement clinique.

TBR 652 : Un autre inhibiteur du CCR5 à l'étude.

Le this compound est unique en raison de sa puissante activité in vitro contre une large gamme de sous-types du VIH et de ses propriétés pharmacocinétiques et pharmacodynamiques favorables . Il a montré des résultats prometteurs dans des essais cliniques, en particulier chez les patients ayant reçu un traitement antérieur .

Vicriviroc (VCV), a CCR5 antagonist, is an investigational compound primarily studied for its efficacy in treating HIV-1 infection. This article delves into the biological activity of this compound, summarizing key research findings, clinical trial outcomes, and resistance patterns.

This compound functions by selectively inhibiting the CCR5 coreceptor on CD4+ T cells, which is crucial for the entry of R5-tropic HIV-1 strains. By blocking this receptor, this compound prevents the virus from infecting host cells. This mechanism positions it as a valuable option in antiretroviral therapy, particularly for patients with CCR5-tropic HIV-1.

Phase 2 Studies

Several phase 2 studies have demonstrated this compound's potential in achieving virologic suppression among treatment-experienced patients:

• Study Design : In a randomized, double-blind study involving 118 subjects, participants received either this compound (at doses of 5 mg, 10 mg, or 15 mg) or placebo. The primary endpoint was the change in plasma HIV-1 RNA levels after 14 days of treatment.
• Results :
  • At 24 weeks, the mean changes in HIV-1 RNA levels were significantly greater in the this compound groups compared to placebo:
    • 5 mg : -1.51 log copies/mL
    • 10 mg : -1.86 log copies/mL
    • 15 mg : -1.68 log copies/mL
    • Placebo : +0.06 log copies/mL (p < .01) .

Long-Term Outcomes

In extended follow-up studies:

• Patients receiving 30 mg of this compound achieved viral loads below 50 copies/mL at rates significantly higher than those on placebo (59% vs. 25%) .
• Over a period of up to 192 weeks, average CD4 counts increased steadily among this compound recipients, indicating sustained immunologic benefit .

Safety Profile

The safety profile of this compound has been generally favorable:

• Adverse events were comparable across treatment groups, with a similar incidence of grade 3/4 adverse events reported .
• However, concerns arose regarding malignancies; six cases were reported among this compound recipients compared to two in the placebo group .

Resistance Patterns

Resistance to this compound has been documented in some patients:

• In the VICTOR-E1 study, five subjects developed VCV-resistant HIV variants after virologic failure .
• Resistance mutations were linked to changes in the V3 loop of the gp160 envelope protein, although no consistent mutation pattern was observed across subjects .

Summary of Key Findings

Basic Research Questions

Q. What experimental models are most appropriate for evaluating Vicriviroc’s mechanism of action as a CCR5 antagonist?

this compound’s mechanism involves blocking HIV-1 entry via CCR5 co-receptor antagonism. In vitro models using CCR5-tropic HIV-1 isolates in peripheral blood mononuclear cells (PBMCs) or cell lines like HEK293/CCR5 are standard for assessing antiviral activity . In vivo models include humanized mice or non-human primates infected with CCR5-tropic HIV-1. Dose-response curves and IC50 values should be calculated using validated assays (e.g., p24 antigen reduction assays) .

Q. How do researchers reconcile discrepancies between tropism assay results (original vs. enhanced-sensitivity) in this compound clinical trials?

Original tropism assays may misclassify dual/mixed (DM) tropic viruses as CCR5-tropic (R5), leading to suboptimal virologic responses. Enhanced-sensitivity assays (e.g., population-based sequencing with deep sequencing) improve detection of minority X4/DM variants. Researchers should retest baseline samples with enhanced assays and stratify outcomes based on updated tropism classifications .

Q. What pharmacokinetic (PK) parameters are critical for optimizing this compound dosing in clinical studies?

Key PK parameters include:

• C_trough : Maintain concentrations above the protein-binding-adjusted IC₉₀ (e.g., 30 mg daily achieves ~50 ng/mL trough levels) .
• Half-life : this compound’s half-life (~24–30 hours) supports once-daily dosing .
• Drug-drug interactions : Co-administration with ritonavir-boosted protease inhibitors (PI/r) increases this compound exposure by ~2-fold, necessitating dose adjustments .

Advanced Research Questions

Q. How should clinical trials be designed to address this compound’s variable efficacy across doses (e.g., 5 mg vs. 15 mg) in treatment-experienced patients?

Phase II trials (e.g., ACTG A5211) used a double-blind, randomized design with dose escalation (5–30 mg) and optimized background regimens (OBR). Key considerations:

• Primary endpoint : Change in HIV-1 RNA at day 14 (short-term activity) .
• Secondary endpoints : CD4 count changes, safety/tolerability at 24–48 weeks .
• Dose selection : Higher doses (15–30 mg) showed sustained virologic suppression, while lower doses (5 mg) had higher failure rates due to emergent X4 tropism .

Q. What methodologies identify this compound resistance in patients with virologic failure despite CCR5-tropic virus?

Resistance mechanisms include:

• Phenotypic assays : Reduced maximal percentage inhibition (MPI) in viral entry assays .
• Genotypic analysis : Env gp160 mutations (e.g., V3 loop changes like G316E/K), though no consistent pattern across subjects .
• Coreceptor switching : Longitudinal monitoring for X4/DM variants via enhanced tropism assays .

Q. How do researchers interpret conflicting data on this compound’s long-term safety, including malignancy risks?

In ACTG A5211, malignancies occurred in 6 this compound recipients vs. 2 placebo recipients, but causality was unclear due to small sample sizes and confounding factors (e.g., advanced HIV disease) . Mitigation strategies:

• Extended follow-up : Monitor malignancy rates in open-label extensions (median follow-up >40 weeks) .
• Comparative safety trials : Use matched cohorts in Phase III studies (e.g., VICTOR-E1) to assess risk-benefit ratios .

Q. Data Analysis & Contradictions

Q. How should researchers address contradictions in this compound’s dose-response relationships across trials?

Conflicting efficacy data (e.g., 15 mg underperforming vs. 10 mg in some studies) may stem from:

• OBR variability : Differential OBR potency across cohorts .
• Tropism assay sensitivity : Enhanced assays reclassify responders/non-responders .
• PK variability : Suboptimal trough levels in certain populations (e.g., CYP3A4 fast metabolizers) . Solutions include stratified analysis by OBR quality and PK-guided dosing.

Q. What statistical approaches are recommended for analyzing this compound’s efficacy in heterogeneous patient populations?

Use mixed-effects models to account for:

• Baseline HIV-1 RNA/CD4 variability : Adjust for baseline viral load and immune status .
• Treatment history : Stratify by prior PI/r exposure or drug resistance profiles .
• Tropism reclassification : Include sensitivity analyses excluding DM/X4 variants detected post-hoc .