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Cenicriviroc Sale

(Synonyms: TAK-652; TBR-652) 目录号 : GC19101

An antagonist of CCR5 and CCR2

Cenicriviroc Chemical Structure

Cas No.:497223-25-3

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实验参考方法

Cell experiment [1]:

Cell lines

human hepatocyte cell line(Huh7.5,Huh7.5JFH1)

Preparation Method

Huh7.5JFH1 cells were plated in 24-well format. After 24 hours, cells were incubated with cenicriviroc.The chemokines MIP-1 alpha MIP-1 beta, and RANTES/CCL5 were quantified in cell supernatants at day 1 and day 3 after addition of Cenicriviroc.

Reaction Conditions

Hepatocyte cell line were treated with Cenicriviroc (0.0025, 0.25, 25 ug/mL) for 24 h.

Applications

HCV core protein levels were significantly reduced in the presence of 0.25 and 25 ug/mL of cenicriviroc.MIP-1 beta expression at day 1 was somewhat lower in the presence of cenicriviroc compared to the no-drug control condition.

Animal experiment [2]:

Animal models

C57BL/6 mice

Preparation Method

Cenicriviroc was administered by oral gavage on Days 1–5. On Day 4, peritonitis was induced via IP injection of TG 3.85% (1 mL/animal) 2 hours post-dose.

Dosage form

5,20,100mg/kg/day, oral gavage

Applications

In vivo mouse model of peritonitis In the TG-induced model of peritonitis, Cenicriviroc treatment led to dose-related decreases in monocyte/macrophage recruitment, of similar or greater magnitude than those observed with dexamethasone.The most potent mediator of chemotaxis for activated macrophages, was reduced following pretreatment with Cenicriviroc at a concentration of 1μM.

References:

[1]. Blackard JT, Kong L, et al. CCR5 receptor antagonism inhibits hepatitis C virus (HCV) replication in vitro. PLoS One. 2019 Oct 29;14(10):e0224523. 

[2]. Lefebvre E, Moyle G, 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.

产品描述

Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors[1].

Cenicriviroc is a small-molecule chemokine receptor antagonist with highly potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity through antagonizing CCR5 as a coreceptor of HIV-1. Cenicriviroc also strongly antagonizes CCR2b, thereby it has potent anti-inflammatory and immunomodulatory effects[2].

Cenicriviroc is a selective inhibitor of SARS-CoV-2 replication.When VeroE6/TMPRSS2 cells were infected with SARS-CoV-2 and incubated in the absence of compounds for 3 days, the cells were completely destroyed by the virus-induced cytopathic effect (Fig. 1 B). Such cell destruction was not observed for the infected cells in the presence of 20 μM Cenicriviroc, although some morphological changes were identified[3].

Repeated intrathecal injections of Cenicriviroc in a dose-dependent manner alleviated neuropathic pain-related behaviors in rats after sciatic nerve injury. Cenicriviroc decreased the activation and/or infiltration of IBA-1-positive cells (microglia/macrophages) in the spinal cord and DRG, and satellite cells in the DRG, and likely as a consequence reduced the level of some important pronociceptive factors (IL-1beta, IL-6, IL-18, and CCL3). Importantly, from a clinical perspective, cenicriviroc enhanced the analgesic potency of morphine and buprenorphine. These beneficial behavioral effects may result, among others, from the influence of cenicriviroc on the mRNA level of opioid receptors (MOR, DOR, KOR, and NOR) at the DRG level. Our results provide the first evidence that simultaneous targeting of CCR2 and CCR5 using cenicriviroc may have great potential for use in neuropathic pain therapies, especially since it is already under clinical trials, though in other health concerns[3].

References:
[1]. Lefebvre E, Moyle G, 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].Okamoto M, Toyama M, et al. The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Oct;182:104902.
[3].Kwiatkowski K, Pawlik K, et al. Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy. Front Immunol. 2020 Dec 21;11:615327.

Cenicriviroc (CVC) 是一种口服的 CCR2/CCR5 双重拮抗剂,对这两种受体具有纳摩尔效力[1]

Cenicriviroc 是一种小分子趋化因子受体拮抗剂,通过拮抗作为 HIV-1 辅助受体的 CCR5,具有高效和选择性的抗人类免疫缺陷病毒 1 型 (HIV-1) 活性。 Cenicriviroc 还强烈拮抗 CCR2b,因此具有有效的抗炎和免疫调节作用[2]

Cenicriviroc 是 SARS-CoV-2 复制的选择性抑制剂。当 VeroE6/TMPRSS2 细胞感染 SARS-CoV-2 并在没有化合物的情况下孵育 3 天时,细胞被病毒诱导的完全破坏细胞病变效应(图 1 B)。在 20 μM Cenicriviroc 存在的情况下,没有观察到受感染细胞的这种细胞破坏,尽管发现了一些形态学变化[3]

以剂量依赖性方式重复鞘内注射 Cenicriviroc 可减轻坐骨神经损伤后大鼠的神经性疼痛相关行为。 Cenicriviroc 降低了脊髓和 DRG 中 IBA-1 阳性细胞(小胶质细胞/巨噬细胞)以及 DRG 中卫星细胞的激活和/或浸润,并可能因此降低了一些重要的伤害感受因子(IL- 1beta、IL-6、IL-18 和 CCL3)。重要的是,从临床角度来看,cenicriviroc 增强了吗啡和丁丙诺啡的镇痛效力。除其他外,这些有益的行为影响可能是由于 cenicriviroc 对 DRG 水平的阿片受体(MOR、DOR、KOR 和 NOR)mRNA 水平的影响。我们的结果提供了第一个证据,表明使用 cenicriviroc 同时靶向 CCR2 和 CCR5 可能具有用于神经性疼痛治疗的巨大潜力,特别是因为它已经在进行临床试验,尽管在其他健康问题上[3] .

Chemical Properties

Cas No. 497223-25-3 SDF
别名 TAK-652; TBR-652
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
分子式 C41H52N4O4S 分子量 696.94
溶解度 DMSO : ≥ 107.5 mg/mL (135.55 mM) 储存条件 Store at -20°C
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Research Update

Current and future pharmacological therapies for NAFLD/NASH

J Gastroenterol2018 Mar;53(3):362-376.PMID: 29247356DOI: 10.1007/s00535-017-1415-1

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.

Cenicriviroc Treatment for Adults With Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study

Hepatology2020 Sep;72(3):892-905.PMID: 31943293DOI: 10.1002/hep.31108

Background and aims: Cenicriviroc (CVC) is a C-C chemokine receptors type 2 and 5 dual antagonist under evaluation for treating liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). Year 1 primary analysis of the 2-year CENTAUR study showed that CVC had an antifibrotic effect without impacting steatohepatitis. Herein, we report the final data from year 2 exploratory analyses.
Approach and results: This was a randomized, controlled study of adults with NASH, nonalcoholic fatty liver disease activity score ≥4, and NASH Clinical Research Network stage 1-3 fibrosis. Participants in arms A and C received CVC 150 mg or placebo, respectively, for 2 years; arm B received placebo in year 1 and switched to CVC in year 2. Liver biopsy was performed at baseline, year 1, and year 2. Of 289 randomized participants, 242 entered year 2. At year 2, 24% of patients who switched to CVC and 17% who remained on placebo achieved ≥1-stage fibrosis improvement and no worsening of NASH (P = 0.37). Twice the proportion on CVC who achieved fibrosis response at year 1 maintained benefit at year 2 (60% arm A versus 30% arm C), including 86% on CVC who had stage 3 fibrosis at baseline. Over 2 years, a similar proportion on CVC or placebo achieved ≥1-stage fibrosis improvement and no worsening of NASH (15% arm A versus 17% arm C). In patients with fibrosis responses, we observed consistent reductions in levels of N-terminal type 3 collagen propeptide and enhanced liver fibrosis scores, while increases in aspartate aminotransferase-to-platelet ratio index and Fibrosis-4 scores were consistently observed in nonresponders. Safety profile was comparable across groups.
Conclusions: CVC was well tolerated, and year 2 data corroborate antifibrotic findings from year 1. The majority on CVC who achieved fibrosis response at year 1 maintained it at year 2, with greater effect in advanced fibrosis. ClinicalTrials.gov number, NCT02217475 (CENTAUR).

A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

Hepatology2018 May;67(5):1754-1767.PMID: 28833331DOI: 10.1002/hep.29477

The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent-to-treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo.
Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754-1767).

Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis

Expert Opin Investig Drugs2018 Mar;27(3):301-311.PMID: 29448843DOI: 10.1080/13543784.2018.1442436

Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is associated with mortality in NAFLD. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis. Areas covered: I summarize preclinical and clinical data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis. In animal models of liver diseases, CVC potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In a phase 2b clinical trial (CENTAUR) on 289 patients with NASH and fibrosis, CVC consistently demonstrated liver fibrosis improvement after 1 year of therapy and had an excellent safety profile, leading to the implementation of a phase 3 trial (AURORA). Expert opinion: Preclinical and clinical data support the development of CVC as a safe and potent antifibrotic agent. However, open questions around CVC are the durability of antifibrotic responses, divergent effects on NASH versus fibrosis, potential long-term concerns and the expected path to approval.

Evolving Role for Pharmacotherapy in NAFLD/NASH

Clin Transl Sci2021 Jan;14(1):11-19.PMID: 32583961DOI: 10.1111/cts.12839

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.