Vicriviroc

合成経路と反応条件

ビクリビロックの合成は、重要な中間体の調製から始まり、複数のステップが含まれています温度、溶媒、触媒などの特定の反応条件は、高収率と純度を確保するために最適化されています .

工業生産方法

ビクリビロックの工業生産は、同様の合成経路に従いますが、商業的な需要を満たすために規模が拡大されています。このプロセスには、規制基準への適合性と一貫性を確保するための厳格な品質管理対策が含まれています。 連続フロー化学や自動合成などの高度な技術が、効率の向上と生産コストの削減に役立つ場合があります .

反応の種類

ビクリビロックは、次のようなさまざまな化学反応を起こします。

酸化： ビクリビロックは酸化されて、主要な代謝産物であるビクリビロックN-オキシドを形成する可能性があります.

還元： 還元反応は、分子内の特定の官能基を修飾するために使用できます。

置換： 置換反応は、ピリミジンコアに置換基を導入または置換するために使用できます.

一般的な試薬と条件

これらの反応で使用される一般的な試薬には、酸化のためのシトクロムP450酵素などの酸化剤、還元のための還元剤、置換反応のための求核剤が含まれます。 温度、pH、溶媒の選択などの反応条件は、所望の結果を得るために注意深く制御されます .

生成される主要な生成物

これらの反応によって生成される主要な生成物には、ビクリビロックN-オキシドと、母体化合物の修飾によって生じる他の代謝産物が含まれます .

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.

ビクリビロックは、CCR5受容体の非競合的アロステリックアンタゴニストとして機能します。これは、CCR5受容体の細胞外表面に近い膜貫通ヘリックス間に位置する疎水性ポケットに結合します。この結合により、受容体のコンフォメーションが変化し、HIV-1 gp120タンパク質がCCR5に結合することができなくなります。 その結果、HIV-1が宿主細胞に侵入することが阻害され、ウイルスのライフサイクルの初期段階が阻止されます .

ビクリビロックは、CCR5阻害剤として知られる化合物のクラスの一部です。類似の化合物には以下が含まれます。

マラビロック： HIV-1感染の治療における臨床使用が承認されている別のCCR5阻害剤.

アプラビロック： 肝毒性の懸念により中止されたCCR5阻害剤.

INCB009471： 臨床開発中のCCR5阻害剤.

TBR 652： 調査中の別のCCR5阻害剤.

ビクリビロックは、さまざまなHIVサブタイプに対して強力なin vitro活性と、良好な薬物動態および薬力学特性を持つことで、ユニークです 。 特に治療歴のある患者において、臨床試験で有望な結果が示されています .

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 .