Maraviroc (UK-427857) is a selective CCR5 antagonist with activity against human HIV.

Maraviroc (UK-427857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity. Maraviroc 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.
Maraviroc (UK-427857) is active (IC₉₀) at low nanomolar concentrations against HIV-1 Ba-L (a lab-adapted R5 strain) when measured in a 5-day antiviral assay using either isolated multiple (pooled) donor PBMC (IC₉₀, 3.1 nM), single-donor PBMC (IC₉₀, 1.8 nM) or PM-1 cells (IC₉₀, 1.1 nM)^[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Clearance values are moderate to high in both rat and dog species following i.v. administration (74 and 21 mL/min/kg, respectively). Maraviroc also has a moderate volume of distribution in both species (4.3 to 6.5 liters/kg). The half-life values of maraviroc are 0.9 h in the rat and 2.3 h in the dog. Following oral administration (2 mg/kg) to the dog, the C_max(256 ng/mL) occurs 1.5 h. post-dose, and the bioavailability is 40%. For the rat, investigation of the concentrations obtain in the portal vein following oral administration indicated that approximately 30% of the administered dose is absorbed from the intestinal tract^[1]. In the DSS/TNBS colitis and in the transfer model, Maraviroc attenuates development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes^[2]

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

513.67

C₂₉H₄₁F₂N₅O

376348-65-1

Room temperature in continental US; may vary elsewhere.

DMSO : 50 mg/mL (97.34 mM; Need ultrasonic)

Ethanol : 6.5 mg/mL (12.65 mM; Need ultrasonic)

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请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
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• 1.

  请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 2.5 mg/mL (4.87 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (4.87 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH₂O 中，得到澄清透明的生理盐水溶液

• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

  Solubility: ≥ 2.5 mg/mL (4.87 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (4.87 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 3.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 2.5 mg/mL (4.87 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (4.87 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• 4.

  请依序添加每种溶剂： 5% DMSO    40% PEG300    5% Tween-80    50% saline

  Solubility: ≥ 2.5 mg/mL (4.87 mM); Clear solution
• 5.

  请依序添加每种溶剂： 5% DMSO    95% (20% SBE-β-CD in saline)

  Solubility: ≥ 2.5 mg/mL (4.87 mM); Clear solution
• 6.

  请依序添加每种溶剂： 1% DMSO    99% saline

  Solubility: ≥ 0.5 mg/mL (0.97 mM); Clear solution

• [1]. Dorr P, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005 Nov;49(11):472

  [2]. Mencarelli A, et al. Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis. Sci Rep. 2016 Aug 5;6:30802.

  [3]. Romero-Sánchez MC, et al. Effect of maraviroc on HIV-disease progression-related biomarkers. Antimicrob Agents Chemother. 2012 Nov;56(11):5858-64.

  [4]. Huilin Mou, et al. NRSF and CCR5 Established Neuron-glia Communication during Acute and Chronic Stresses. Journal of Drug Metabolism & Toxicology. January 10, 2016.

Binding of ¹²⁵I-labeled MIP-1α, MIP-1β, and RANTES to CCR5 is measured essentially 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; Boehringer) 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. Appropriate maraviroc dilutions are added to each well to a final volume of 100 μL, the assay plates incubated for 1 h, and the contents filtered through preblocked and washed Unifilter plates which are counted following overnight drying^[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

HEK-293 cell aliquots (100 μL at 1×10⁶ cells/mL) are plated into poly-D-lysine-coated plates and incubated at 37°C overnight. A 1:1 mix of soluble recombinant human CD4 (sCD4) (diluted to 4.5 nM in culture medium) and HIV-1 gp120 is incubated at room temperature for 15 min prior to its addition to PBS-washed cells in the presence of dilutions of maraviroc to enable IC₅₀ determination. The assay plates are incubated at 37°C for 1 h and washed. Eu³⁺-labeled anti-gp120 antibody (1/500 dilution in assay buffer) is added to each well (50 μL) and incubated for 1 h. The plate is washed three times with wash buffer prior to the addition of enhancement solution (200 μL/well) and measurement of Eu³⁺ fluorescence (Victor²multilabel counter; “Europium” protocol). Nonspecific binding is taken as the fluorescence measured for gp120 incubated with cells in the absence of preincubation with sCD4^[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Rats and Dogs^[1]
Preclinical pharmacokinetic studies are carried out with maraviroc following a single intravenous and oral administration to both male Sprague-Dawley rats (1 mg/kg of body weight given intravenously [i.v.] and 10 mg/kg given orally [p.o.]; n=2) and male beagle dogs (0.5 mg/kg i.v. and 2 mg/kg p.o; n=4). Plasma samples are taken for up to 24 h postdose, and the concentrations of unchanged maraviroc are determined using a specific high-performance liquid chromatography-tandem mass spectrum assay.
Mice^[2]
Splenocytes are collected from 6-10 week old CCR5^-/- mice or wild-type controlmice (n=8 per group) and naive CD4⁺ CD45RB^high T-cells are isolated by cell sorting. A total of 3×10⁵ CD45RB^high cells are then injected intravenously into Rag1^-/- mice that are subsequently weighed and assessed for fecal score every 20 days to evaluate IBD development. To investigate whether Maraviroc rescues from intestinal inflammation induced by transfer colitis, Rag1^-/- mice are injected with CD4⁺ CD45RB^-/- T-cells and 34 days later randomized into either a control group (no further treatment, n=6) or treatment with Maraviroc, 50 mg/kg/d Maraviroc per os (n=4) for 3 weeks, 5 d/week.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Dorr P, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005 Nov;49(11):472

  [2]. Mencarelli A, et al. Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis. Sci Rep. 2016 Aug 5;6:30802.

  [3]. Romero-Sánchez MC, et al. Effect of maraviroc on HIV-disease progression-related biomarkers. Antimicrob Agents Chemother. 2012 Nov;56(11):5858-64.

  [4]. Huilin Mou, et al. NRSF and CCR5 Established Neuron-glia Communication during Acute and Chronic Stresses. Journal of Drug Metabolism & Toxicology. January 10, 2016.