Aplaviroc (AK 602)
(Synonyms: 4-[4-[[(3R)-1-丁基-3-[(R)-环己基羟基甲基]-2,5-二氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基]甲基]苯氧基]苯甲酸,AK 602; GSK 873140; GW 873140) 目录号 : GC32336
Aplaviroc (AK 602) (AK 602) 是一种 SDP 衍生物，是一种 CCR5 拮抗剂，对 HIV-1Ba-L、HIV-1JRFL 和 HIV-1MOKW 的 IC50 值为 0.1-0.4 nM。
Cas No.:461443-59-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Aplaviroc, a SDP derivative, is a CCR5 antagonist, with IC50s of 0.1-0.4 nM for HIV-1Ba-L, HIV-1JRFL and HIV-1MOKW.
Aplaviroc (AK602) is identified as the most potent agent among newly designed and synthesized SDP derivatives. Aplaviroc exerts potent activity against three wild-type R5 HIV-1 strains (HIV-1Ba-L, HIV-1JRFL and HIV-1MOKW) with IC50 values of 0.1 to 0.4 nM. It is of note that Aplaviroc is substantially more potent than two previously published CCR5 inhibitors, E921/TAK-779 and AK671/SCH-C. The activity of Aplaviroc's anti-HIV-1 is limited and similar to that seen for zidovudine. Moreover, Aplaviroc suppresses the infectivity and replication of two HIV-1MDR variants, HIV-1MM and HIV-1JSL, at extremely low concentrations (IC50 values of 0.4 to 0.6 nM), while these two R5 HIV-1 variants are less susceptible to zidovudine, nelfinavir, and saquinavir. Aplaviroc binds to CCR5 with high affinity. The Kd values thus determined for Aplaviroc, E913, E921/TAK-779, and AK671/SCH-C are 2.9±1.0, 111.7±3.5, 32.2±9.6, and 16.0±1.5 nM, respectively. Aplaviroc potently blocks rgp120/sCD4 binding to CCR5 with an IC50 value of 2.7 nM. These results suggest that the potent activity of Aplaviroc against R5 HIV-1 stems from its binding to ECL2B and/or its vicinity with high affinity, resulting in inhibition of gp120/CD4 binding to CCR5[1].
[1]. Maeda K, et al. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J Virol. 2004 Aug;78(16):8654-62.
| Cas No. | 461443-59-4 | SDF | |
| 别名 | 4-[4-[[(3R)-1-丁基-3-[(R)-环己基羟基甲基]-2,5-二氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基]甲基]苯氧基]苯甲酸,AK 602; GSK 873140; GW 873140 | ||
| Canonical SMILES | O=C(O)C1=CC=C(OC2=CC=C(CN(CC3)CCC3(N(CCCC)C([C@@H]([C@@H](C4CCCCC4)O)N5)=O)C5=O)C=C2)C=C1 | ||
| 分子式 | C33H43N3O6 | 分子量 | 577.71 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.731 mL | 8.6549 mL | 17.3097 mL |
| 5 mM | 0.3462 mL | 1.731 mL | 3.4619 mL |
| 10 mM | 0.1731 mL | 0.8655 mL | 1.731 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Evaluation of the drug interaction potential of Aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail
J Clin Pharmacol 2006 May;46(5):577-87.PMID:16638741DOI:10.1177/0091270006287291.
Aplaviroc is a novel CCR5 antagonist, a class of compounds under investigation as viral entry inhibitors for the treatment of human immunodeficiency virus infection. A modified Cooperstown 5+1 cocktail was used to assess the drug interaction potential of Aplaviroc. Fifteen healthy subjects were administered single oral doses of caffeine (CYP1A2), warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) alone (reference treatment) and during steady-state administration of Aplaviroc (400 mg every 12 hours, test treatment). Metabolite-to-parent area under the plasma concentration versus time curve (AUC) ratios (paraxanthine/caffeine and 5-hydroxyomeprazole/omeprazole), oral clearance (S-warfarin), AUC (midazolam), and metabolite-to-parent urinary excretion ratio (dextrorphan/dextromethorphan) were determined. The test-to-reference treatment ratios (geometric mean ratio and 90% confidence interval) were caffeine, 1.06 (0.97-1.17); S-warfarin, 0.93 (0.76-1.15); omeprazole, 1.07 (0.98-1.16); dextromethorphan, 1.17 (0.97-1.42); midazolam, 1.30 (1.04-1.63). No significant inhibition of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 enzyme activity was observed. Mild inhibition of CYP3A isozymes should not preclude the use of concomitant CYP3A substrates in future clinical studies with Aplaviroc.
Antiviral activity and safety of Aplaviroc, a CCR5 antagonist, in combination with lopinavir/ritonavir in HIV-infected, therapy-naïve patients: results of the EPIC study (CCR100136)
HIV Med 2009 Feb;10(2):116-24.PMID:19200175DOI:10.1111/j.1468-1293.2008.00660.x.
Background: This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist Aplaviroc (APL) in antiretroviral-naïve patients harbouring R5- or R5X4-tropic virus. Methods: A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed. Results: This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability. Conclusions: While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.
In vitro and clinical investigation of the relationship between CCR5 receptor occupancy and anti-HIV activity of Aplaviroc
J Clin Pharmacol 2008 Oct;48(10):1179-88.PMID:18676693DOI:10.1177/0091270008322178.
Aplaviroc (GW873140) binds specifically to human cellular CC chemokine receptor 5 (CCR5) and demonstrates potent anti-human immunodeficiency virus activity in vitro in the subnanomolar range. In vitro studies show that Aplaviroc selectively inhibits the binding of a particular monoclonal antibody, 45531, to CCR5. Based on this observation, a flow cytometry-based assay was developed to determine percentage CCR5 receptor occupancy (RO). CCR5 receptor occupancy was Aplaviroc concentration-dependent and related to anti-human immunodeficiency virus activity in vitro. In the clinical setting, CCR5 receptor occupancy in peripheral blood was >98% in all subjects within 2 to 3 hours of dosing, which is consistent with the peak plasma concentrations of drug. Longitudinal analysis in the drug washout period revealed the time to 50% CCR5 receptor occupancy averaged >100 hours, in both human immunodeficiency virus-positive and human immunodeficiency virus-negative subjects, substantially longer than the plasma pharmacokinetic half-life of 3 hours. The duration of CCR5 receptor occupancy appeared to be dose-dependent and associated with antiviral activity as measured by plasma human immunodeficiency virus RNA nadir following 10 days of multiple dose administration. These data demonstrate that the analysis of CCR5 receptor occupancy, in addition to conventional plasma-based pharmacokinetic measures, provides an informative tool to assist in evaluating the pharmacodynamic and antiviral effects of cellular CC chemokine receptor antagonists.
Virologic failure in therapy-naive subjects on Aplaviroc plus lopinavir-ritonavir: detection of Aplaviroc resistance requires clonal analysis of envelope
Antimicrob Agents Chemother 2009 Mar;53(3):1124-31.PMID:19075068DOI:10.1128/AAC.01057-08.
The CCR100136 (EPIC) study evaluated the antiviral activity of the novel CCR5 entry inhibitor Aplaviroc in combination with lopinavir-ritonavir in drug-naïve human immunodeficiency virus type 1-infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met the protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, Aplaviroc susceptibility, and env sequencing were performed on plasma at day 1 and at the time of virologic failure. Molecular evolutionary analyses were also performed. Treatment-emergent resistance to Aplaviroc or lopinavir-ritonavir was not observed at the population level. However, Aplaviroc resistance was detected prior to therapy at both the clonal and population levels in one subject with virologic failure and in six subjects in a minority (<50%) of clones at day 1 or at the time of virologic failure. Reduced Aplaviroc susceptibility manifested as a 50% inhibitory concentration curve shift and/or a plateau. Sequence changes in the clones with Aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones at day 1 and at the time of virologic failure were not phylogenetically distinct. Two subjects with virologic failure had a population tropism change from CCR5- to dual/mixed-tropic during treatment. Virologic failure during a regimen of Aplaviroc and lopinavir-ritonavir may be associated with Aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.
Hepatotoxicity observed in clinical trials of Aplaviroc (GW873140)
Antimicrob Agents Chemother 2008 Mar;52(3):858-65.PMID:18070967DOI:10.1128/AAC.00821-07.
Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.