Cenicriviroc mesylate

Category	Human immunodeficiency Virus (HIV)
CAS	497223-28-6
Description	Cenicriviroc is an inhibitor of CCR2 and CCR5 receptors, allowing it to function as an entry inhibitor which prevents the virus from entering into a human cell as an experimental drug candidate for the treatment of HIV infection.

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Product Information

Synonyms	TAK-652 mesylate; TAK 652 mesylate; TBR-652 mesylate; TBR 652 mesylate
Molecular Weight	793.051
Molecular Formula	C42H56N4O7S2
Canonical SMILES	CCCCOCCOC1=CC=C(C=C1)C2=CC3=C(C=C2)N(CCCC(=C3)C(=O)NC4=CC=C(C=C4)S(=O)CC5=CN=CN5CCC)CC(C)C.CS(=O)(=O)O
InChI	InChI=1S/C41H52N4O4S.CH4O3S/c1-5-7-22-48-23-24-49-38-15-10-32(11-16-38)33-12-19-40-35(25-33)26-34(9-8-21-44(40)28-31(3)4)41(46)43-36-13-17-39(18-14-36)50(47)29-37-27-42-30-45(37)20-6-2;1-5(2,3)4/h10-19,25-27,30-31H,5-9,20-24,28-29H2,1-4H3,(H,43,46);1H3,(H,2,3,4)/b34-26+;
InChIKey	IXPBPUPDRDCRSY-WNRKZQPVSA-N
Purity	99.04%
Solubility	In Vitro: DMSO : 100 mg/mL(126.10 mM;Need ultrasonic) In Vivo: 1.Add each solvent one by one:5% DMSO >> 40%PEG300 >> 5%Tween-80 >> 50% saline Solubility: 2.5 mg/mL (3.15 mM); Clear solution; Need ultrasonic 2.Add each solvent one by one:10% DMSO >> 40%PEG300 >> 5%Tween-80 >> 45% saline Solubility: ≥ 2.08 mg/mL (2.62 mM); Clear solution 3.Add each solvent one by one:10% DMSO >> 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.08 mg/mL (2.62 mM); Clear solution
Appearance	Light yellow to yellow (Solid)
Storage	4°C, sealed storage, away from moisture * In solvent : -80°C, 6 months -20°C, 1 month (sealed storage, away from moisture)
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. 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.
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. 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.
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) mode.
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)