Maraviroc

Humanized BALB/c-Rag2 / gammac / and BALB/c-Rag1 / gammac / (RAG-hu) mice

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

0-1 uM

ca.64 ug

3.3 nM, 3.3 nM, 3.3 nM, 3.3 nM, 3.3 nM, 3.3 nM

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]

Inhibition of chemokine binding to CCR5, Binding of 125I-labeled MIP-1alpha, MIP-1beta, 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 ug of membrane protein is used in each well of a 96-well plate). 125I-radiolabeled MIP-1alpha, MIP-1beta, 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 uL, the assay plates incubate for 1 hour, and the contents filter through preblocked and washed Unifilter plates which are counted following overnight drying.

513, 67

, , Dr Mikhail Menshikov of Cardiology Research Center, Maravirocpurchased from Selleck, Analysis of receptor mechanisms mediating the induction of MMP-9 expression in THP-1 cells by AFP. Maraviroc, an inhibitor of chemokine receptor CCR5, was added to the cells in the indicated concentrations 1 hour before addition of 50 g/ml AFP or 150 ng/ml RANTES. After 24 hours of cell stimulation, conditioned media were collected and analyzed for MMP-9 activity by the method of zymography

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO