Cenicriviroc Mesylate
(Synonyms: TAK-652 Mesylate; TBR-652 Mesylate) 目录号 : GC35650An antagonist of CCR5 and CCR2
Cas No.:497223-28-6
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.50%
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Cell experiment: | 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 experiment: | 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). 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[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. |
Cenicriviroc is an orally bioavailable antagonist of C-C chemokine receptor type 5 (CCR5) and CCR2 that inhibits binding of macrophage inflammatory protein 1α (MIP-1α; IC50 = 2.3 nM) and monocyte chemotactic protein 1 (MCP-1; IC50 = 5.9 nM), respectively, in CHO cells.1 Cenicriviroc is also an antagonist of CCR3 and CCR4 (IC50s = 2.4 and 1.1 μM, respectively), however, it does not inhibit agonist binding to CCR1 or CCR7 at concentrations up to 10 μM. At a concentration of 100 nM, cenicriviroc completely inhibits replication of R5 HIV-1 in U87.CD4.CCR5 cells. Cenicriviroc inhibits replication of the R5 HIV-1 strains JR-FL and KK in peripheral blood mononuclear cells (PBMCs) with EC50 values ranging from 21 to 210 pM and 33 to 91 pM, respectively. In vivo, cenicriviroc (20 mg/kg per day) reduces collagen deposition, levels of collagen type 1 protein and mRNA expression, and non-alcoholic fatty liver disease activity score in a mouse model of non-alcoholic steatohepatitis (NASH).2 It also reduces collagen type 1 protein levels, mRNA expression, and collagen deposition in a mouse model of unilateral ureter obstruction and a rat model of thioacetamide-induced liver fibrosis.
1.Baba, M., Takashima, K., Miyake, H., et al.TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humansAntimicrob. Agents Chemother.49(11)4584-4591(2005) 2.Lefebvre, E., Moyle, G., Reshef, R., et al.Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosisPLoS One11(6):e0158156(2016)
Cas No. | 497223-28-6 | SDF | |
别名 | TAK-652 Mesylate; TBR-652 Mesylate | ||
Canonical SMILES | O=C(/C1=C/C2=CC(C3=CC=C(OCCOCCCC)C=C3)=CC=C2N(CC(C)C)CCC1)NC4=CC=C([S@](CC5=CN=CN5CCC)=O)C=C4.OS(=O)(C)=O | ||
分子式 | C42H56N4O7S2 | 分子量 | 793.05 |
溶解度 | DMSO: 100 mg/mL (126.10 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.261 mL | 6.3048 mL | 12.6095 mL |
5 mM | 0.2522 mL | 1.261 mL | 2.5219 mL |
10 mM | 0.1261 mL | 0.6305 mL | 1.261 mL |
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Fumaric acid microenvironment tablet formulation and process development for crystalline Cenicriviroc Mesylate, a BCS IV compound
Mol Pharm 2013 Nov 4;10(11):4005-15.PMID:23941629DOI:10.1021/mp400286s
Cenicriviroc Mesylate (CVC) is a potent dual antagonist of C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) in phase 2b development as an entry inhibitor for HIV-1 infection treatment.1,2 CVC is a weak base exhibiting BCS IV characteristics with a highly pH dependent solubility profile (>100 mg/mL for pH < 2 and <0.2 μg/mL for pH > 4) and low Caco-2 cell line permeability. Previous tablet formulations of CVC, including spray-dried dispersion and a wet granulation with citric acid, had been found unacceptable for commercial use due to chemical and physical instability or unacceptably high excipient loading precluding fixed-dose combinability. A high drug loading, 26% (w/w), acidic microenvironment tablet formulation with fumaric acid solubilizer (1:1 CVC/fumaric acid) and a dry granulation process was developed iteratively through a sequence of prototypes characterized by beagle dog absorption studies, focused beam reflectance measurement (FBRM), dynamic vapor sorption (DVS), and accelerated stability testing. The fumaric acid based dry granulated product demonstrated a mean bioavailability comparable to an oral solution dose in a dog model. Stability and moisture sensitivity of the formulation were improved via the dry granulation process technique and the use of fumaric acid. It is hypothesized that the observed slow dissolution kinetics of fumaric acid prolongs an acidic microenvironment around the agglomerated CVC crystals and excipients leading to increased CVC dissolution and thereby absorption. The fumaric acid formulation also demonstrated absorption resilience to gastric pH extremes in a dog model. This optimized formulation and process enables CVC to be a viable candidate for current HIV treatment paradigms of single once daily fixed-dose combination products.