Maraviroc-UK-427857-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEMaravirocCat. No.: HY-13004CAS No.: 376348-65-1Synonyms: UK-427857分式: CHFNO分量: 513.67作靶点: CCR; HIV作通路: GPCR/G Protein; Immunology/Inflammation; Anti-infection储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month

2、BIOLOGICAL ACTIVITY物活性 Maraviroc是选择性的CCR5拮抗剂，具有抑制 HIV 的活性。IC50 & Target MIP-1-CCR5 RANTES-CCR5 MIP-1-CCR5 HIV-1 (Ba-L)3.3 nM (IC50, in HEK- 5.2 nM (IC50, in HEK- 7.2 nM (IC50, in HEK- 1.1 nM (IC50, in PM-1293 cell membrane) 293 cell membrane) 293 cell membrane) cells)体外研究 Maraviroc is a selective CC

3、R5 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-1, MIP-1 and RANTES. Maraviroc is active(IC90) at low nanomola

4、r 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.体内研究Clearance values are moderate to high in both rat and dog speci

5、es following i.v. administration (74 and 21mL/min/kg, respectively). Maraviroc also has a moderate volume of distribution in both species (4.3 to 6.5liters/kg). The half-life values of maraviroc are 0.9 h in the rat and 2.3 h in the dog. Following oraladministration (2 mg/kg) to the dog, the Cmax(25

6、6 ng/mL) occurs 1.5 h. post-dose, and the bioavailability is40%. For the rat, investigation of the concentrations obtain in the portal vein following oral administrationindicated that approximately 30% of the administered dose is absorbed from the intestinal tract 1. In the1/3 Master of Small Molecu

7、les 您边的抑制剂师www.MedChemEDSS/TNBS colitis and in the transfer model, Maraviroc attenuates development of intestinal inflammation byselectively reducing the recruitment of CCR5 bearing leukocytes 2PROTOCOLKinase Assay 1 Binding of 125I-labeled MIP-1, MIP-1, and RANTES to CCR5 is measured essentially us

8、ing intact HEK-293 cells stably expressing the receptor or membrane preparations thereof. Briefly, cells are resuspended inbinding buffer (50 mM HEPES containing 1 mM CaCl2, 5 mM MgCl2, and 0.5% bovine serum albumin BSAand adjusted to pH 7.4) to a density of 2106 cells/mL. For membrane preparations,

9、 phosphate-bufferedsaline (PBS)-washed cells are resuspended in lysis buffer (20 mM HEPES, 1 mM CaCl2, 1 tabletCOMPLETE 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 protei

10、n concentration of0.25 mg/mL (12.5 g of membrane protein is used in each well of a 96-well plate). 125I-radiolabeled MIP-1,MIP-1, and RANTES are prepared and diluted in binding buffer to a final concentration of 400 pM in theassay. Appropriate maraviroc dilutions are added to each well to a final vo

11、lume of 100 L, the assay platesincubated for 1 h, and the contents filtered through preblocked and washed Unifilter plates which are countedfollowing overnight drying 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 HEK-293 cell aliquots (

12、100 L at 1106 cells/mL) are plated into poly-D-lysine-coated plates and incubatedat 37C overnight. A 1:1 mix of soluble recombinant human CD4 (sCD4) (diluted to 4.5 nM in culturemedium) and HIV-1 gp120 is incubated at room temperature for 15 min prior to its addition to PBS-washedcells in the presen

13、ce of dilutions of maraviroc to enable IC50 determination. The assay plates are incubatedat 37C for 1 h and washed. Eu3+-labeled anti-gp120 antibody (1/500 dilution in assay buffer) is added toeach well (50 L) and incubated for 1 h. The plate is washed three times with wash buffer prior to the addit

14、ionof enhancement solution (200 L/well) and measurement of Eu3+ fluorescence (Victor2multilabel counter;“Europium” protocol). Nonspecific binding is taken as the fluorescence measured for gp120 incubated withcells in the absence of preincubation with sCD4 1.MCE has not independently confirmed the ac

15、curacy of these methods. They are for reference only.Animal Rats and Dogs 1Administration 12 Preclinical pharmacokinetic studies are carried out with maraviroc following a single intravenous and oraladministration to both male Sprague-Dawley rats (1 mg/kg of body weight given intravenously i.v. and

16、10mg/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 samplesare taken for up to 24 h postdose, and the concentrations of unchanged maraviroc are determined using aspecific high-performance liquid chromatography-tandem mass spectrum assay.Mice 2Splenocyte

17、s are collected from 6-10 week old CCR5-/- mice or wild-type controlmice (n=8 per group) andnaive CD4+ CD45RBhigh T-cells are isolated by cell sorting. A total of 3105 CD45RBhigh cells are theninjected intravenously into Rag1-/- mice that are subsequently weighed and assessed for fecal score every20

18、 days to evaluate IBD development. To investigate whether Maraviroc rescues from intestinal inflammationinduced by transfer colitis, Rag1-/- mice are injected with CD4+ CD45RB-/- T-cells and 34 days laterrandomized into either a control group (no further treatment, n=6) or treatment with Maraviroc,

19、50 mg/kg/d2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEMaraviroc per os (n=4) for 3 weeks, 5 d/week.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Front Pharmacol. 2017 May 3;8:230. Drug Metab Dispos. 2019 Jul 2. pii: dmd.119.087684. Cy

20、tokine. 2018 Oct;110:70-77. J SUN Yatsen Univ (Med Sci). 2018,39(1):41-47. Journal of Drug Metabolism & Toxicology. January 10, 2016.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Dorr P, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005 Nov;49(11):4722. Menca