tcsc0032631 Cenicriviroc Mesylate

Cenicriviroc is a dual CCR2/CCR5 antagonist, also inhibits both HIV-1 and HIV-2, and displays potent anti-inflammatory and antiinfective activity.

IC50 & Target: CCR2/CCR5^[1]

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].