Maraviroc 化学構造
分子量: 513.67

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Quality Control & MSDS

製品説明

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製品の説明

生物活性

製品説明 Maraviroc は、MIP-1α、MIP-1βとRANTESのケモカイン受容体CCR5阻害剤で、IC50 がそれぞれ 3.3 nM、7.2 nM と 5.2 nMです。
ターゲット MIP-1α MIP-1β RANTES
IC50 3.3 nM 7.2 nM 5.2 nM [1]
In vitro試験 Maraviroc inhibits MIP-1β-stimulated γ-S-GTP binding to HEK-293 cell membranes, indicating its ability to inhibit chemokine-dependent stimulation of GDP-GTP exchange at the CCR5/G protein complex. Maraviroc also inhibits the downstream event of chemokine-induced intracellular calcium redistribution, with IC50s ranging from 7 to 30 nM obtained against MIP-1β, MIP-1α and RANTES. In the same experiments, Maraviroc does not trigger release of intracellular calcium at concentrations up to 10 μM, indicating that it is devoid of CCR5 agonist activity. Consistent with this, Maraviroc fails to induce CCR5 internalization. Maraviroc is active at low nanomolar concentrations against HIV-1 Ba-L. Maraviroc inhibits all 200 pseudotyped viruses with a geometric mean IC90 of 13.7 nM. [1]
In vivo試験 The half-life values of Maraviroc are 0.9 hour in the rat and 2.3 hours in the dog. Following oral administration (2 mg/kg) to the dog, the Cmax (256 ng/ml) occurred 1.5 hours post-dose, and the bioavailability is 40%. For the rat, approximately 30% of the administered dose is absorbed from the intestinal tract. [1] Female RAG-hu mice are challenged vaginally with HIV-1 an hour after intravaginal application of the Maraviroc gel. Maraviroc gel treated mice are fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. Vaginal administration of Maraviroc fully protects mice against HIV-1 vaginal challenge. While there is a clear pattern of CD4 T cell decline in placebo-gel treated and viral challenged mice, their levels are stable in mice receiving Maraviroc gel. [2]
臨床試験 Maraviroc has entered in a Phase IV clinical trial in the treatment of human immunodeficiency virus (HIV).
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Inhibition of chemokine binding to CCR5 Binding of 125I-labeled MIP-1α, MIP-1β, and RANTES to CCR5 is measured using intact HEK-293 cells stably expressing the receptor or membrane preparations thereof. Briefly, cells are resuspended in binding buffer (50 mM HEPES containing 1 mM CaCl2, 5 mM MgCl2, and 0.5% bovine serum albumin [BSA] and adjusted to pH 7.4) to a density of 2 × 106 cells/ml. For membrane preparations, phosphate-buffered saline (PBS)-washed cells are resuspended in lysis buffer (20 mM HEPES, 1 mM CaCl2, 1 tablet COMPLETE per 50 mL, pH 7.4) prior to homogenization in a Polytron hand-held homogenizer, ultracentrifugation (40,000× g for 30 min), and resuspension in binding buffer to a protein concentration of 0.25 mg/mL (12.5 μg of membrane protein is used in each well of a 96-well plate). 125I-radiolabeled MIP-1α, MIP-1β, and RANTES are prepared and diluted in binding buffer to a final concentration of 400 pM in the assay. Maraviroc dilutions are added to each well to a final volume of 100 μL, the assay plates incubate for 1 hour, and the contents filter through preblocked and washed Unifilter plates which are counted following overnight drying.

細胞アッセイ: [1]

細胞株 PHA-stimulated PBMC or PM-1 cells
濃度 0-1 μM
反応時間 5 days or 7 days
実験の流れ Drug susceptibility assays are performed in 24-well tissue culture plates. Duplicate eight-point dilution series of Maraviroc are prepared in DMSO and medium to yield a final DMSO concentration of 0.1% (vol/vol) in the assay. PHA-stimulated PBMC or PM-1 cells are infected with virus for 1 hour at 37 °C. Cells are subsequently washed once, and 3.6 × 105 PBMC or 2.0 × 105 PM-1 cells are added to each well of assay plates containing diluted Maraviroc. Plates are incubated for 5 days (lab-adapted strains) or 7 days (primary isolates) at 37 °C in a humidified 5% CO2 (vol/vol) atmosphere.

動物実験: [2]

動物モデル Humanized BALB/c-Rag2−/−γc−/− and BALB/c-Rag1−/−γc−/− (RAG-hu) mice
製剤 Dissolved in phosphate-buffered saline, sterile-filtered and adjusted to a final concentration of 4 mg/mL (7.8 mM). A 3.4% gel preparation of hydroxyl-ethyl cellulose (HEC) is added to achieve a final concentration of 5 mM Maraviroc in 2.2% HEC gel.
投薬量 ~64 μg
投与方法 A 25 μL volume of the gel formulation is carefully applied in to the vaginal vault of mice.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Maraviroc SDF
分子量 513.67
化学式

C29H41F2N5O

CAS No. 376348-65-1
保管 2年-20℃
6月-80℃in solvent
別名 UK-427857
溶解度 (25°C) * In vitro DMSO 100 mg/mL (194.67 mM)
エタノール 100 mg/mL (194.67 mM)
<1 mg/mL (<1 mM)
In vivo 2% DMSO+corn oil 10mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 4,4-difluoro-N-((S)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)-1-phenylpropyl)cyclohexanecarboxamide

カスタマーフィードバック (2)


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Rating
Source Cancer Res, 2012, 72(15), 3839-50. Maraviroc purchased from Selleck
Method 3D invasion assays
Cell Lines Hs578T, SUM-159 cells
Concentrations 100 nM
Incubation Time 24 h
Results To evaluate the functional relevance of CCR5 in cellular migration and invasion, it tested the effects of maraviroc and vicriviroc in 3D invasion assays. Using 2 different cell lines, we found that both Maraviroc inhibited FBS-induced breast cancer cell invasion at the clinically relevant concentration of 100 nmol/L.

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Rating
Source 2010, Dr. Johanna Weiss of University Hospital Heidelberg. Maraviroc purchased from Selleck
Method zymography
Cell Lines THP-1 cells
Concentrations 0-50 μM
Incubation Time 24 h
Results Analysis of receptor mechanisms mediating the induction of MMP-9 expression in THP-1 cells by AFP.

文献中の引用 (5)

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