[Description]:
Cenicriviroc is a dual CCR2/CCR5 antagonist, also inhibits both HIV-1 and HIV-2, and displays potent anti-inflammatory and antiinfective activity.
[Related Catalog]:
[Target]
CCR5:0.29 nM (IC50)
CCR2:5.9 nM (IC50)
R5 HIV-1:0.024-0.08 nM (IC50, in PBMCs)
R5 HIV-2:0.03-0.98 nM (IC50, in PBMCs)
[In Vitro]
Migration of mouse monocytes in response to carbon tetrachloride (CCL2) is reduced following pre-treatment with Cenicriviroc Mesylate (CVC) at a concentration of 1 μM. Compare to untreated and unstimulated cells, the average fold change in migrating cells (±SD) is 0.8±0.2 (p>0.05) and 0.7±0.4 (p>0.05) for CCL2-stimulated cells treated with Cenicriviroc Mesylate and unstimulated cells treated with Cenicriviroc Mesylate, respectively[1]. Phenotypic susceptibility testing shows, for the four R5-tropic HIV-2 isolates, a median EC50 for Cenicriviroc Mesylate of 0.39 nM (0.03, 0.33, 0.45 and 0.98 nM). The dual-tropic and the X4-tropic HIV-2 strains are resistant to Cenicriviroc Mesylate with EC50 at >1000 nM, and Maximum percentages of inhibition (MPI) at 33% and 4%, respectively[2].
[In Vivo]
Cenicriviroc Mesylate (CVC) treatment leads to dose-related decrease in monocyte/macrophage recruitment, of similar or greater magnitude than those observed with dexamethasone (positive control), and achieving statistical significance at doses ≥20 mg/kg/day (p<0.05). Compare to the vehicle-control group, peritoneal lavage monocyte/macrophage counts are decreased by: 5.7%, 45.2%, 76.5%, 26.0% and 38.1% for Cenicriviroc Mesylate 5 twice daily (BID), Cenicriviroc Mesylate20 twice daily (BID), Cenicriviroc Mesylate100 BID, Cenicriviroc Mesylate20 once-daily (QD) and dexamethasone, respectively. Exposure to Cenicriviroc Mesylate is dose-related and correlated with the decrease in monocyte/macrophage recruitment, with Cenicriviroc Mesylate appearing to be more effective when given BID versus QD, in line with the higher plasma concentrations achieved with BID dosing and the known short half-life in mice (~2 hours). Compare to dexamethasone, monocyte/macrophage-count decreases are significantly more pronounced with Cenicriviroc Mesylate100 BID (62.1% greater reduction, p<0.001). A slight decrease in body weight is observed in the unilateral ureter obstruction (UUO) model (5%, Cenicriviroc Mesylate20 vs. UUO control on Day 5, p<0.05), and in the liver-to-body weight ratio in the Rat model of thioacetamide (TAA) model[1].
[Cell Assay]
Mouse monocyte migration in response to Cenicriviroc Mesylate (CVC) treatment is assessed ex vivo in triplicate. Thioglycollate (TG) is injected intraperitoneally into male C57BL/6 mice (n=3; 8 to 10 weeks of age) and activated macrophages are collected 48 hours later by peritoneal lavage. Cells are incubated for 2 hours in the presence of 1 μM Cenicriviroc Mesylate. Cells are harvested from the lower compartment and analyzed by flow cytometry to enumerate F4/80+CD11b+ macrophages. Results are analyzed using FlowJo software[1].
[Animal admin]
Male C57BL/6 mice (n=44; 8 to 10 weeks of age) are allocated to receive treatments via oral gavage (PO) on Days 1 to 5 in the following groups: non-disease control, vehicle control twice daily (BID), Cenicriviroc Mesylate 5 mg/kg/day (CVC5) BID, Cenicriviroc Mesylate 20 mg/kg/day (CVC20) BID, Cenicriviroc Mesylate 100 mg/kg/day (CVC100) BID, Cenicriviroc Mesylate 20 mg/kg once-daily (QD), and positive control dexamethasone 1 mg/kg QD. On Day 4, peritonitis is induced via IP injection of thioglycollate (TG) 3.85% (1 mL/animal) 2 hours post-dose in all groups except non-disease controls. Study endpoints include: peritoneal lavage cell counts and pharmacokinetic (PK) evaluation. Animals are sacrificed 48 hours post-TG injection by isoflurane inhalation, and peritoneal lavage and blood samples (0.7 mL) are collected. Differential cell counts are assessed in peritoneal lavage samples. A 0.3 mL aliquot of the blood sample is processed to plasma for pharmacokinetic (PK) analysis[1].
[References]
[1]. Lefebvre E, et al. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One. 2016 Jun 27;11(6):e0158156.
[2]. Visseaux B, et al. Cenicriviroc, a Novel CCR5 (R5) and CCR2 Antagonist, Shows In Vitro Activity against R5 Tropic HIV-2 Clinical Isolates. PLoS One. 2015 Aug 6;10(8):e0134904.
[3]. Lalezari J, et al. Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in HIV-1-infected, treatment-experienced, CCR5 antagonist-naive subjects. J Acquir Immune Defic Syndr. 2011 Jun 1;57(2):118-25.
[4]. Baba M, et al. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob Agents Chemother. 2005 Nov;49(11):4584-91.
[Related Small Molecules]