CCR5 ( IC50 = 0.29 nM ); CCR2 ( IC50 = 5.9 nM ); R5 HIV-1 ( IC50 = 0.024-0.08 nM ); R5 HIV-2 ( IC50 = 0.03-0.98 nM )

体外活性：Cenicriviroc（以前称为 TAK-652 或 TBR-652）是一种新型口服生物活性 CCR2/CCR5 双重拮抗剂，它还能抑制 HIV-1 和 HIV-2，并具有潜在的治疗艾滋病毒感染。 TAK-652 在纳摩尔浓度下抑制 RANTES（受激活、正常 T 细胞表达和分泌调节）、巨噬细胞炎症蛋白 1α (MIP-1α) 和 MIP-1β 与 CCR5 表达细胞的结合。 TAK-652 还可以抑制单核细胞趋化蛋白 1 (MCP-1) 与表达 CCR2b 的细胞的结合。然而，其对配体与其他趋化因子受体结合的抑制作用有限。 TAK-652 对使用 CCR5（R5）的 HIV-1 有活性，但对使用 CXCR4（X4）的 HIV-1 完全没有活性。激酶测定：Cenicriviroc 可防止人类免疫缺陷病毒 1 型 (HIV-1) 进入细胞，对于测试的 4 个 R5 HIV-2 临床分离株，有效浓度 50% EC50 为 0.03、0.33、0.45 和 0.98 nM。双向性和 X4 向性 HIV-2 毒株对西尼昔韦罗具有耐药性，EC50 > 1000 nM，MPI 分别为 33% 和 4%。细胞测定：AK-652 在纳摩尔浓度下抑制 RANTES（受激活、正常 T 细胞表达和分泌调节）、巨噬细胞炎症蛋白 1α (MIP-1α) 和 MIP-1β 与 CCR5 表达细胞的结合。 TAK-652 还可以抑制单核细胞趋化蛋白 1 (MCP-1) 与表达 CCR2b 的细胞的结合。

Cenicriviroc (≥20 mg/kg/day) 显着减少体内单核细胞/巨噬细胞的募集。在这些剂量下，cenicriviroc 显示出抗纤维化作用，在三种纤维化动物模型中显着减少胶原蛋白沉积以及 1 型胶原蛋白和 mRNA 表达。在 NASH 模型中，cenicriviroc 显着降低非酒精性脂肪肝疾病活动评分。 Cenicriviroc 治疗对身体或肝/肾重量没有显着影响。

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Cenicriviroc（CVC）在剂量≥20mg/kg/天时，显著降低了体内单核细胞/巨噬细胞的募集（p<0.05）。在这些剂量下，CVC显示出抗纤维化作用，在三种纤维化动物模型中，胶原沉积（p<0.05）和1型胶原蛋白和mRNA表达显著降低。在NASH模型中，CVC显著降低了非酒精性脂肪肝活动评分（与对照组相比，p<0.05）。CVC治疗对体重或肝肾重量没有显著影响。 结论：CVC在一系列动物纤维化模型中显示出强大的抗炎和抗纤维化活性，支持人类对纤维化疾病的测试。需要进一步的实验研究来阐明CVC抗纤维化作用的潜在机制。一项针对NASH和肝纤维化成年人的2b期研究已全部纳入（CENTAUR研究652-2-203；NCT02217475）。[1]

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受试者按每剂量水平4:1的比例随机分配到Cenicriviroc/TBR-652（25、50、75、100或150 mg）或安慰剂组，每天服用一次，持续10天。在第40天测量HIV-1 RNA和CD4细胞计数与基线的变化，在第10天测量单核细胞趋化蛋白-1（MCP-1）、高敏C反应蛋白（hs-CRP）和IL-6的变化。药代动力学数据采用非房室统计进行分析。记录实验室和临床不良事件（AE）和心电图变化。 结果：25、50、75和150 mg剂量的HIV-1 RNA值的最大中值降低分别为-0.7、-1.6、-1.8和-1.7 log10拷贝/毫升。所有变化都很显著。达到最低点的中位时间为10-11天。抑制一直持续到治疗后。50mg和150mg剂量组的平均MCP-1在第10天显著增加。对CD4细胞计数、hs-CRP和IL-6水平的影响可以忽略不计。TBR-652总体上是安全的，耐受性良好，没有因不良事件而停药。 结论：TBR-652在所有剂量下均能显著降低HIV-1 RNA。MCP-1水平的显著升高表明CCR2的阻断作用很强。TBR-652通常耐受良好，没有剂量限制性不良事件。药效学表明，TBR-652作为一种未经强化的每日一次口服CCR5拮抗剂，具有潜在的重要CCR2介导的抗炎作用，值得进一步研究。[4]

对于测试的四种 R5 HIV-2 临床分离株，Cenicriviroc 以 50% EC50 为 0.03、0.33、0.45 和 0.98 nM 的有效浓度阻止 HIV-1 进入细胞。双向性和 X4 向性 HIV-2 毒株中的 Cenicriviroc 耐药性对于 EC50 为 >1000 nM，对于 MPI 分别为 33% 和 4%。

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趋化因子结合试验。[5]
之前已经描述了测试化合物对趋化因子结合抑制的测定程序。简而言之，表达CCR5的CHO细胞与不同浓度的Cenicriviroc (CVC)/TAK-652在结合缓冲液（含20 mM HEPES和0.5%牛血清白蛋白的Ham’s F-12培养基，pH 7.2）中孵育，该缓冲液含有200 pM 125I活化调节、正常T细胞表达和分泌（RANTES）、125I巨噬细胞炎性蛋白1α（MIP-1α）或125I-MIP-1β。结合反应在室温下进行40分钟。通过用冷磷酸盐缓冲盐水（PBS）洗涤两次无细胞配体来终止结合反应。用闪烁计数器 记录细胞相关放射性。以类似的方式进行了Cenicriviroc（CVC）/TAK-652对125I-RANTES与CCR1、125I-单核细胞趋化蛋白1（MCP-1）与CCR2b、125I-嗜酸性粒细胞趋化因子与CCR3、125I-胸腺和活化调节趋化因子（TARC）与CCR4以及125I-MIP-3β与CCR7结合的抑制作用的检测。

对小鼠单核细胞响应甲磺酸 Cenicriviroc (CVC) 治疗的迁移进行了三项独立评估。在雄性 C57BL/6 小鼠（n = 3；8-10 周龄）中，腹膜内注射巯基乙酸盐 (TG)。 48小时后，通过腹腔灌洗提取活化的巨噬细胞。将 1 μM 甲磺酸西尼基韦罗溶液添加到细胞中并孵育两小时。流式细胞仪通过分析从下室提取的细胞来计数 F4/80⁺CD11b⁺ 巨噬细胞的数量。使用 FlowJo 软件对结果进行分析[1]。

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Cenicriviroc表型活性已使用PBMC表型敏感性试验对四种R5-、一种X4-和一种双嗜性HIV-2临床原发分离株进行了测试。所有分离物都是通过共培养PHA激活的PBMC获得的，这些PBMC来自法国HIV-2队列中不同的HIV-2感染的CCR5拮抗剂未成年患者，并且之前使用相同的方案进行了马拉韦敏感性测试。使用Ghost（3）细胞系通过表型分析确定HIV-2趋向性。结果：对于所测试的4株R5 HIV-2临床分离株，西尼利韦罗的有效浓度50%EC50分别为0.03、0.33、0.45和0.98 nM，与马拉韦罗的观察浓度相似：分别为1.13、0.58、0.48和0.68 nM。西尼利韦罗的最大抑制百分比（MPI）为94、94、93和98%，与马拉韦罗的观察结果相似（分别为93、90、82、100%）。双嗜性和X4嗜性HIV-2菌株对西尼利韦罗具有耐药性，EC50>1000 nM，MPI分别为33%和4%。 结论：在这项首次评估HIV-2对西尼利韦罗敏感性的研究中，我们观察到其对HIV-2 R5嗜性毒株的体外活性与马拉韦罗相似。因此，在有限的HIV-2治疗药物库中，西尼利韦可提供每日一次的治疗机会。有必要进行临床研究。[3]

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雄性C57BL/6小鼠腹腔注射TG，48小时后腹腔灌洗收集活化的巨噬细胞。使用带有 5 μm 孔径聚碳酸酯过滤器的 Transwell1 室来测定趋化性。简而言之，细胞用 1 nM CCL2 和/或 1 μM Cenicriviroc（溶解在 0.5% 乙酸二甲亚砜中，并用无血清 Roswell Park Memorial Institute-1640 培养基和 0.5% 牛血清白蛋白按 1:1000 稀释）培养两小时）。使用 3 激光 BD FACSCanto，从下室提取细胞并进行流式细胞术分析，以计算 F4/80+CD11b+ 巨噬细胞的数量。使用FlowJo软件对结果进行分析。

Male C57BL/6 mice (n = 44; 8–10 weeks old) are divided into 5 groups and given oral gavage (PO) treatments on Days 1–5. These groups include 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, and Cenicriviroc Mesylate 20 mg/kg once-daily (10 QD). With the exception of the non-disease controls, all groups undergo IP injections of thioglycollate (TG) 3.85% (1 mL/animal) two hours post-dose to induce peritonitis on Day 4[1].

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Male C57BL/6 mice (n = 44; 8–10 weeks old) are divided into the following groups and given oral gavage (PO) treatments on Days 1–5: non-disease control, twice-daily (BID) vehicle control, 5 mg/kg/day (Cenicriviroc5) BID, 20 mg/kg/day (Cenicriviroc20) BID, 100 mg/kg/day (Cenicriviroc100) BID, Cenicriviroc20 QD, and positive control (1 mg/kg QD)—a corticosteroid that has been shown to reduce inflammation in a number of animal models. On Day 4, all groups except the non-disease controls receive an IP injection of TG 3.85% (1 mL/animal) two hours post-dose to induce peritonitis.

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Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. [1]

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Single-dose safety and pharmacokinetics in humans.[5]
A double-blind phase I trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of a single oral administration of TAK-652 in humans. Twenty-four healthy volunteers were enrolled in this study (two for a placebo and six for each dose), and three doses (25, 50, and 100 mg) of TAK-652 were administered orally as a solution to individuals in a fasted state. The TAK-652 solution was formulated in 0.5% (wt/vol) methylcellulose with 0.1% (wt/vol) Polysorbate 80 and 2 mM hydrochloric acid in distilled water. The placebo solution was 0.5% (wt/vol) methylcellulose with 0.1% (wt/vol) Polysorbate 80 and 2 mM hydrochloric acid in distilled water. Doses were selected based on allometric scaling of preclinical pharmacokinetic data and considerations of preclinical toxicology (no observed adverse effects). Screening was performed in the 3-week period prior to dosing, and poststudy assessments were carried out at 5 to 7 days postdosing. Safety and tolerability were evaluated by physical examinations (screening and poststudy), recording of vital signs (screening, predose, 1, 2, 4, 8, and 24 h postdose, and poststudy), electrocardiograms (ECG; screening, predose, 2, 6, and 24 h postdose, and poststudy), clinical laboratory evaluations (hematology, serum chemistry, and urinalysis; screening, predose, 24 h postdose, and poststudy), and recording of adverse events (predose, 3, 12, and 24 h postdose, and poststudy). Serial blood samples were collected to determine the plasma concentration of TAK-652. Blood samples were collected prior to drug administration (0 h) and then 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h after administration. The samples were immediately processed, and the plasma concentration of TAK-652 was quantified by liquid chromatography/tandem mass spectrometry. The lower limit of TAK-652 quantification in plasma was 0.05 ng/ml. Pharmacokinetic parameters were estimated by noncompartmental procedures using WinNonlin, version 3.2, Enterprise. The maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) for each subject were calculated from the measured concentrations. The area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC0-tz) for each subject was calculated from the measured concentrations by the trapezoidal rule.

At all doses, peak plasma concentrations of TBR-652 were reached within 3–4 hours (Table 2). Helmert comparisons showed that steady-state concentrations (Css) were reached on day 8. The area under the concentration-time curve (AUC0–24) and peak plasma concentration (Cmax) after log-normal (ln) transformation at 24 hours indicated that the increase in these parameters was greater than dose-dependent. [1] Figure 5 shows the mean plasma concentrations of TAK-652 at each dose from 30 minutes to 24 hours after administration. At all doses, the drug was detectable in plasma at both 30 minutes and 24 hours after administration. Table 6 lists the estimated pharmacokinetic parameters after a single oral administration in healthy volunteers. Overall, TAK-652 has good oral absorption and a long plasma half-life. At 24 hours after administration of 25 mg, its plasma concentration was 7.2 ng/ml, equivalent to 9.1 nM [5].

Within the studied dose range, TBR-652 was generally safe and well-tolerated. The most common adverse events (AEs) occurring during treatment in subjects receiving the active pharmaceutical ingredient included: gastrointestinal disorders (n = 19, 43%); systemic disorders (n = 11, 25%); neurological disorders (n = 10, 23%); respiratory, thoracic, and mediastinal disorders (n = 10, 23%); infections and parasitic diseases (n = 7, 16%); and mental disorders (n = 5, 11%). Most adverse events in subjects receiving TBR-652 were mild (n = 24) or moderate (n = 5) in severity. Only one subject receiving TBR-652 experienced a serious adverse event, a shoulder abscess, which was determined by the investigator to be a non-serious adverse event unrelated to the study drug, requiring no treatment, and without sequelae. No life-threatening adverse events occurred, the trial was not terminated due to adverse events, and no deaths occurred. All adverse events were determined to be clearly related to the investigational drug. Table 3 lists the adverse events reported as possibly or very likely related to the investigational drug. Most adverse events resolved without intervention. Only 4 subjects in the TBR-652 group required concurrent administration of other medications due to adverse events assessed as possibly related to the investigational drug. These adverse events were: hydrocodone and acetaminophen for abdominal pain in the 25 mg dose group; acetaminophen for headache in the 50 mg dose group; ondansetron for nausea in the 100 mg dose group; and ibuprofen for headache and nausea in one subject in the 150 mg dose group. All adverse events requiring treatment were considered very likely related to the investigational drug. [4]

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No subjects withdrew from the trial due to adverse events among the 24 treated subjects. A total of 4 subjects reported 6 clinical adverse events. Of the 6 adverse events, two dose-independent symptoms (headache and fatigue) were considered to be possibly related to the investigational drug. The remaining four minor adverse events (headache, nasopharyngitis, decreased sensation, and dizziness) appeared to be unrelated to TAK-652 administration, but this conclusion requires further investigation. No treatment- or dose-related trends were observed in serum chemistry, hematology, and urinalysis data during the study. No dose-related trends were also observed in supine systolic blood pressure, diastolic blood pressure, and pulse rate. No treatment- or dose-related trends were observed in vital signs or electrocardiograms of any subject during the study. Of particular note was the absence of evidence of QTc interval prolongation at any dose of TAK-652. No clinically significant changes were observed in electrocardiogram morphology in any subject receiving any dose. No clinically significant changes were observed at the end of the study. Therefore, single oral administration of TAK-652 (25, 50, and 100 mg solutions) is safe and well-tolerated in healthy male subjects. [5]

[1]. 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]. Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies. Antimicrob Agents Chemother. 2015 Nov 2;60(1):437-5.

[3]. 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.

[4]. 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.

[5]. 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.

Cenicriviroc mesylate is the mesylate form of cenicriviroc, a highly bioavailable dual inhibitor that inhibits human CC chemokine receptors type 2 (CCR2; CD192) and type 5 (CCR5; CD195), exhibiting potential immunomodulatory, anti-inflammatory, and antiviral activities. After oral administration, cenicriviroc specifically binds to and inhibits the activation of CCR2 and CCR5. This inhibits the CCR2/CCR5-mediated signal transduction pathway and may suppress inflammatory processes. G protein-coupled chemokine receptors CCR2 and CCR5 are expressed on the surface of monocytes and macrophages, stimulating their migration and infiltration; they play crucial roles in inflammation and autoimmune diseases. Furthermore, cenicriviroc inhibits human immunodeficiency virus (HIV)-1 invasion by interacting with the CCR5 co-receptor.

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Cenicriviroc belongs to the benzoxazole octane class of compounds. Its chemical name is (5Z)-1,2,3,4-tetrahydro-1-benzoxazole octane, with 2-methylpropyl, N-{4-[(S)-(1-propyl-1H-imidazol-5-yl)methylsulfinyl]phenyl}formamido, and 4-(2-butoxyethoxy)phenyl substitutions at positions 1, 5, and 8, respectively. It is a potent chemokine 2 and 5 receptor antagonist and is currently under development for the treatment of liver fibrosis caused by non-alcoholic steatohepatitis (NASH) in adults. It exhibits dual activity as a chemokine receptor 5 antagonist, anti-HIV drug, chemokine receptor 2 antagonist, antirheumatic drug, and anti-inflammatory drug. It is a diether, imidazole compound, sulfoxide, aromatic ether, secondary amide, and benzoxazole octane compound.
Cenicriviroc is being investigated for the treatment of HIV infection/AIDS, AIDS-related dementia syndrome, non-alcoholic steatohepatitis, human immunodeficiency virus (HIV), and HIV-1-related cognitive-motor syndrome.
Cenicriviroc is a dual inhibitor with high oral bioavailability that inhibits human CC chemokine receptors type 2 (CCR2; CD192) and type 5 (CCR5; CD195), possessing potential immunomodulatory, anti-inflammatory, and antiviral activities. After oral administration, cenicriviroc specifically binds to and blocks the activation of CCR2 and CCR5. This inhibits the CCR2/CCR5-mediated signal transduction pathway and may suppress inflammatory processes. G protein-coupled chemokine receptors CCR2 and CCR5 are expressed on the surface of monocytes and macrophages and stimulate their migration and infiltration; they play a crucial role in inflammation and autoimmune diseases. Furthermore, cenicriviroc also inhibits HIV-1 entry through interaction with the CCR5 co-receptor.
See also: Cenicriviroc mesylate (note moved to).

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Drug Indications
Treatment of non-alcoholic steatohepatitis (NASH)
Cenicriviroc is a CCR5 antagonist that blocks human immunodeficiency virus type 1 (HIV-1) from entering cells.The CCR5 binding region of the HIV-1 envelope glycoprotein is an important target for neutralizing antibodies (NAbs); therefore, mutations conferring resistance to cenicriviroc may affect its sensitivity to NAbs. This study investigated the relationship between cenicriviroc resistance and NAbs resistance using HIV-1 variants induced in vitro to produce resistance to either cenicriviroc or NAbs. The cenicriviroc-resistant variant KK652-67 (KK strain passaged 67 times in the presence of increasing concentrations of cenicriviroc) is sensitive to NAbs targeting the V3 loop, CD4-inducible region (CD4i), and CD4-binding site (CD4bs), while the wild-type (WT) parent HIV-1 strain KKWT, which produced the cenicriviroc-resistant strain KK652-67, is resistant to these NAbs. The V3 region of KK652-67 is crucial for cenicriviroc resistance and is a key factor in the high sensitivity of the V3, CD4i, and CD4bs epitopes to neutralizing antibodies (NAbs). Furthermore, inducing a variant resistant to V3 NAb 0.5γ and CD4i NAb 4E9C from the cenicriviroc-resistant strain KK652-67 resulted in a phenotype reverting to the cenicriviroc-sensitive phenotype similar to that of the parent strain KKWT. Resistance to 0.5γ and 4E9C was caused by three new amino acid substitutions in the V3 and C3 regions, namely R315K, G324R and E381K, which are located near the amino acid substitutions that confer resistance to cenicriviroc. Importantly, these amino acid changes in the CCR5 binding region also led to the phenotype reverting to the cenicriviroc sensitive phenotype. These results indicate that there are some key amino acid residues that make resistance to cenicriviroc incompatible with resistance to neutralizing antibodies. This means that cenicriviroc and neutralizing antibodies may limit the emergence of resistant variants of each other. [2] The first small molecule CCR5 antagonist, TAK-779, failed to be developed as an anti-human immunodeficiency virus (anti-HIV-1) drug due to its low oral bioavailability. TAK-652 is a derivative of TAK-779 with high oral bioavailability and potent anti-HIV-1 activity. TAK-652 inhibits the binding of RANTES (molecules that activate and regulate the expression and secretion of normal T cells), macrophage inflammatory protein 1α (MIP-1α), and MIP-1β to CCR5-expressing cells at nanomolar concentrations. TAK-652 also inhibits the binding of monocyte chemokine 1 (MCP-1) to CCR2b-expressing cells. However, its inhibitory effect on the binding of ligands to other chemokine receptors is limited. TAK-652 is effective against (R5) HIV-1 virus using the CCR5 receptor but completely ineffective against (X4) HIV-1 virus using the CXCR4 receptor. This compound is effective against R5 HIV-1 clinical isolates containing resistance mutations to reverse transcriptase and protease inhibitors, with mean half-maximal effective concentrations (EC50) and EC90 of 0.061 nM and 0.25 nM, respectively. Furthermore, recombinant R5 viruses carrying different subtypes (A to G) of the envelope protein showed similar sensitivity to TAK-652. Single oral doses of up to 100 mg of TAK-652 were safe and well-tolerated in humans. The compound exhibited favorable pharmacokinetic properties, with plasma concentrations remaining at 7.2 ng/ml (9.1 nM) even 24 hours after a 25 mg dose. Therefore, TAK-652 is a promising novel HIV-1 entry inhibitor. [5]

C42H56N4O7S2

793.05

792.359

C, 63.61; H, 7.12; N, 7.06; O, 14.12; S, 8.09

497223-28-6

Cenicriviroc; 497223-25-3; 497223-22-0 (Cenicriviroc Sulfone)

11285791

Light yellow to yellow solid powder

168

2

10

17

55

1150

1

S(CC1=CN=CN1CCC)(C1C=CC(=CC=1)NC(C1=CC2C=C(C3C=CC(=CC=3)OCCOCCCC)C=CC=2N(CCC1)CC(C)C)=O)=O.S(C)(=O)(=O)O |t:20|

IXPBPUPDRDCRSY-YLZLUMLXSA-N

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+;/t50-;/m0./s1

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: 2.5 mg/mL (3.15 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (2.62 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (2.62 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。