A8311-5mg | Maraviroc [376348-65-1] Clinisciences

Background

Maraviroc is a potent and selective antagonist of Chemokine Receptor CCR5 [1].

CCR5 is a receptor for chemokines and exists on the surface of white blood cells that are involved in the immune system. Many forms of HIV enter and infect host cells through CCR5 [1].

Maraviroc is a potent and selective inhibitor of CCR5 with potent anti-HIV-1 activity. Maraviroc exhibited antiviral activity against all CCR5-tropic HIV-1 viruses tested with IC90 of 2.0 nM. In HeLa P4 cells, maraviroc inhibited binding of viral envelope gp120 to CCR5 with IC50 value of 11 nM and prevented the membrane fusion events, which were necessary for viral entry. While, maraviroc didn’t affect CCR5 levels or associated intracellular signaling, which suggested it is an antagonist of CCR5 [1].

In a patient infected with both R5-tropic and X4-tropic HIV-1 viruses, treatment with maraviroc suppressed all R5-tropic viruses. And the R5-tropic viruses were replaced by more X4-tropic viruses [2].

References:
[1]. Dorr P, Westby M, Dobbs S, 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, 49(11): 4721-4732.
[2]. Symons J, van Lelyveld SF, Hoepelman AI, et al. Maraviroc is able to inhibit dual-R5 viruses in a dual/mixed HIV-1-infected patient. J Antimicrob Chemother, 2011, 66(4): 890-895.

Product Citation

1. Beilei Chen, Pingping Cao, et al. "Maraviroc, an inhibitor of chemokine receptor type 5, alleviates neuroinflammatory response after cerebral Ischemia/reperfusion injury via regulating MAPK/NF-κB signaling." Int Immunopharmacol. 2022 Jul;108:108755. PMID: 35395466
2. van Attekum MH, Terpstra S, et al. "Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia." Oncogene. 2017 Feb 13. PMID: 28192408

Chemical Properties

Storage	Desiccate at -20°C
M.Wt	513.67
Cas No.	376348-65-1
Formula	C₂₉H₄₁F₂N₅O
Synonyms	UK-427857; Selzentry; Celsentri
Solubility	≥25.7 mg/mL in DMSO; insoluble in H2O; ≥48 mg/mL in EtOH
Chemical Name	4,4-difluoro-N-[(1S)-3-[(1S,5R)-3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide
SDF	Download SDF
Canonical SMILES	CC1=NN=C(N1C2CC3CCC(C2)N3CCC(C4=CC=CC=C4)NC(=O)C5CCC(CC5)(F)F)C(C)C
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1]:
Inhibition of chemokine binding to CCR5	Binding of 125I-labeled MIP-1α, MIP-1β, and RANTES to CCR5 was measured using intact HEK-293 cells stably expressing the receptor or membrane preparations thereof. Briefly, cells were 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 were 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 mins), and resuspension in binding buffer to a protein concentration of 0.25 mg/mL (12.5 μg of membrane protein was used in each well of a 96-well plate). 125I-radiolabeled MIP-1α, MIP-1β, and RANTES were prepared and diluted in binding buffer to a final concentration of 400 pM in the assay. Maraviroc dilutions were added to each well to a final volume of 100 μL, the assay plates were incubated for 1 hr, and the contents were filtered through preblocked and washed Unifilter plates which were then counted and dried overnight.
Cell experiment [1]:
Cell lines	PBMC or PM-1 cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months.
Reaction Conditions	0.01 ~ 10 nM; 5 days
Applications	In PBMC or PM-1 cells, Maraviroc was active against HIV-1 Ba-L even at low nanomolar concentrations, with the IC90 values ranging from 1.1 nM to 3.1 nM. Meanwhile, Maraviroc showed no effect on cell proliferation at concentrations up to 10 μM.
Animal experiment [1]:
Animal models	Rats and dogs
Dosage form	74 and 21 ml/min/kg, respectively; i.v.
Applications	In rats and dogs, Maraviroc showed moderate to high clearance values, as well as moderate volumes of distribution (4.3 to 6.5 liters/kg). For rats and dogs, the half-life values of Maraviroc were 0.9 hr and 2.3 hrs, respectively.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Dorr P, Westby M, Dobbs S, 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, 49(11): 4721-4732.

Biological Activity

Description	Maraviroc is an antagonist of CCR5 for MIP-1α, MIP-1β and RANTES with IC50 of 3.3 nM, 7.2 nM and 5.2 nM, respectively.
Targets	MIP-1α	MIP-1β	RANTES
IC50	3.3 nM	7.2 nM	5.2 nM