HCV NS5A (EC50 = 9 pM-50 pM)

体外活性：BMS-790052 是迄今为止报道的最有效的 HCV 复制抑制剂之一。对于 HCV 基因型 1a 和 1b 复制子，BMS-790052 的平均 EC50 值分别为 50 和 9 pM。 BMS-790052 显示出至少 105 的治疗指数 (CC50/EC50)，并且对一组 10 种 RNA 和 DNA 病毒无活性，EC50 高于 10 μM。这证实了 BMS-790052 对 HCV 的特异性。在含有 HCV 基因型 1b 复制子的 Huh7 细胞中，BMS-790052 可阻断短暂和稳定的 HCV 基因组复制，EC50 值范围为 1-15 pM。 BMS-790052（100 pM 或 1 nM）已被证明可以改变 NS5A 的亚细胞定位和生化分级。 BMS-790052 抑制含有 HCV 基因型 4 NS5A 基因的杂交复制子，EC50 为 7-13 pM。 NS5A 的残基 30 是杂种复制子中 BMS-790052 介导的抗性的重要位点。激酶测定：Daclatasvir 是一种有效的 HCV NS5A 蛋白抑制剂，针对基因型 1a 和 1b 复制子的平均 EC50 值分别为 50 和 9 pM。细胞测定：通过使用具有复制能力的 1a 或 1b 复制子构建杂交体来评估达卡他韦对基因型的抗病毒活性，其中整个 NS5A 编码区或来自不同基因型的 NS5A 的前 100 个氨基酸替换亲本复制子的相应序列。据报道，达卡他韦对所有 HCV 基因型均高度有效，半数有效浓度 (EC50) 范围为 9 至 146 pM

人源化肝脏嵌合小鼠的肝脏嵌合率估计超过 40%，静脉注射 100 µL HCV 阳性人血清样本。接种后，每 1-4 周从颈外静脉采集一次血液。 HCV RNA 水平通过 COBAS TaqMan HCV 测试在 100 倍稀释的血清中测量，测量范围较低为 3.2 log IU/mL 血清。 HCV RNA 血清水平达到平台水平后，给小鼠口服以下药物之一，每天一次，持续 4 周：40 mg/kg Asunaprevir 加 30 mg/kg Daclatasvir，15 mg/kg Ledipasvir 加 50 mg/kg。 kg GS-558093 和 50 mg/kg GS-558093 加 400 mg/kg Telaprevir。

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在一项随机、双盲、安慰剂对照、单次递增剂量研究中，Daclatasvir/BMS-790052以6个剂量水平给健康、非HCV感染的受试者服用，剂量范围为1至200 mg口服溶液。该化合物安全，耐受性良好，最高可达200 mg，无临床相关不良反应。口服给药后，Daclatasvir/BMS-790052很容易被吸收，剂量比例暴露在研究的剂量范围内，所有受试者的药物浓度都大于基因型1a和1b的蛋白质结合调整后的EC90，如复制子试验所测，在24小时及以上 h给药后（图3）。（蛋白质结合调整后的EC90数字来自对添加人血清对复制子抗病毒活性的影响的分析。在40%的人血清存在的情况下，BMS-790052的EC90为383 pM（0.28纳克 ml-1）用于基因型1a复制子和49 pM（0.04纳克 ml-1）用于基因型1b复制子。)[1]

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在一项随机、双盲、安慰剂对照、单次递增剂量研究中，对基因型1慢性HCV受试者以1、10和100的剂量给予Daclatasvir/BMS-790052 mg口服溶液。除两名受试者在10岁时感染了HCV基因型1a外，所有受试者均感染了HCV mg和三名受试者在100 感染基因型1b的mg患者。BMS-790052在单次口服剂量高达100 mg。具体而言，没有死亡、严重不良事件、因不良事件或临床相关不良反应而停药。头痛是最常见的不良事件，四名受试者在服用BMS-790052后报告了这一事件。在HCV感染的受试者中，BMS-790052的平均血浆消除半衰期为10至14 h、 血浆药物水平与非HCV感染者相似。单次口服10-100剂后 mg BMS-790052，所有受试者的24小时血浆浓度均高于HCV基因型1a和1b的十倍蛋白结合校正EC90，这表明每天给药一次的可能性。测量血浆HCV RNA水平长达6 给药后几天；从给药到144的平均下降 h给药后如图4所示。单毫克剂量的BMS-790052产生的平均值为1.8 log10减少（范围0.2-3.0 log10）在HCV病毒载量中的测量值为24 给药后h。10和100 mg剂量产生了更大的抗病毒作用，平均血浆病毒RNA下降了3.2log10（范围2.9-4.0 log10）和3.3 log10（范围2.7-3.6 log10），分别为24 h给药后。此外，100 mg剂量导致HCV RNA平均最大下降3.6 log10（范围3.0-4.1 log10），在两名感染基因型1b病毒的受试者中观察到长期的抗病毒反应，HCV RNA测量值达到定量下限（小于25 IU ml-1）1例，35例 IU 另一组在144小时时测得ml-1。对给药后基线（T0）、24（T24）和144（T144）小时采集的样本进行基因型分析后发现，一般来说，需要显著降低病毒载量才能检测到主要的HCV变异。在使用体外复制子系统鉴定的氨基酸位置观察到置换（补充表12-14）：基因型1a的M28T、Q30H/R和L31M，基因型1b的Y93H，结果表明复制子系统在评估体内对抑制剂压力的抗性方面是有用的。其中只有一名受试者的随访样本，结果显示HCV RNA已恢复到接近基线水平；然而，没有对该样本进行基因型分析。根据BMS-790052的体外复制子效力，可以预期，感染基因型1b的受试者的HCV RNA会出现更大、更持续的下降（平均3.6 log10减少（范围3.1-4.0 log10）和平均值3.1 log10减少（范围2.7–3.4 log10）在HCV病毒载量中的测量值为24 10和100之后的h mg剂量）比基因型1a感染的受试者（平均1.8 log10减少（范围0.2-3.0 log10），平均2.9 log10减少（范围2.9–3.0 log10）和平均值3.6 log10减少（范围3.5-3.6 log10）在HCV病毒载量中的测量值为24 1、10和100后的h mg剂量）。接受10和100治疗的受试者的平均下降率 mg剂量的BMS-790052与36 mg剂量相似 给药后h，接受100μg/ml给药的受试者的平均下降幅度更大，持续时间更长 mg。接受1 mg BMS-790052的HCV RNA平均下降幅度低于10和100 mg（图4）。然而，需要多剂量研究来确定病毒下降第一阶段后最大抗病毒效果的最佳剂量范围。使用Pearson相关系数探讨了HCV RNA从基线的最大下降与药物药代动力学暴露之间的关系。所有估计的Pearson相关系数均高于0.65，表明log10 HCV RNA和对数药代动力学暴露（BMS-790052 Cmax、AUC（0-T）、AUC、INF、C12和C24）的最大下降呈正相关；也就是说，log10 HCV RNA的最大下降幅度随着暴露于Daclatasvir/BMS-790052而增加[1]。

肽 (Ac-Asp-Glu-Asp [EDANS]-Glu-Glu-Abu-[COO] Ala-Ser-Lys [DABCYL]-NH2) 含有荧光供体 {EDANS, 5-[(2-氨乙基)氨基]萘-1-磺酸}靠近肽的一端，受体{DABCYL，4-[(4-二甲基氨基)苯基]偶氮)苯甲酸}靠近另一端。供体和受体之间的分子间共振能量转移淬灭了肽的荧光，但当 NS3 蛋白酶切割肽时，产物从共振能量转移淬灭中释放出来。随着更多底物被 NS3 蛋白酶裂解，供体的荧光随着时间的推移而增强。检测试剂由 20 μM FRET 肽、150 mM NaCl 和 5× 荧光素酶细胞培养裂解液（用 dH₂O 稀释至 1×）组成。在 96 孔板中，添加 HCV-Huh-7 细胞并贴壁过夜（每孔 1×10⁴ 细胞）。第二天将 BMS-790052 添加到孔中后，将板孵育 72 小时。之后，用 PBS 清洗板，并通过向每个孔中添加 30 μL 前面提到的 FRET 肽测定试剂来准备 FRET 测试。通过使用 Cytoflor 4000 仪器在动力学模式下读取板来获取信号，该仪器被编程为在 340 nm（激发）/490 nm（发射）下以自动模式运行 20 个循环或更少。 FRET 完成后，每孔加入 40 μL 荧光素酶底物，并评估荧光素酶的量。

约 12 小时前，将 BMS-790052 添加到 96 孔板中，该板已在 200 µL 培养基中接种了 HCV 复制子细胞。孵育 72 小时后，检查细胞板的细胞毒性和复制活性。使用 CellTiter-Blue 测量细胞毒性后，除去培养基和染料，将板倒置，并用纸巾吸干剩余的液体。海肾荧光素酶用于测量 HCV 基因型 1a 细胞系的复制活性。向每个孔中添加 1× 海肾荧光素酶裂解缓冲液 (30 µL) 后，将板孵育 15 分钟，并轻轻摇动。然后使用 Top Count 光度计检测信号，该光度计配置为在添加 40 µL 海肾荧光素酶底物后进行光发射定量。仅使用 DMSO 的孔计算每个细胞系的 100% 活性；将含有化合物的孔的平均值除以含有DMSO的孔的平均值，以确定每个抑制剂浓度的活性百分比。

At the termination of experiments, all mice were euthanized by CO2 inhalation. To evaluate in vivo efficacy of antiviral agents on HCV, NOD/SCID mice bearing HCV-replicating Huh7 xenografts were used21. Briefly, HCV RNA-transfected cells mixed with Matrigel were injected into the large lobes of the livers of anesthetized immunodeficient NOD/SCID male mice (5 weeks of age, 18–20 g body weight). Four weeks after implantation, compounds dissolved in saline were orally administered to mice using a feeding needle. Serum HCV titer was monitored by RT-qPCR.[Sci Rep. 2018 Aug 20;8(1):12469]

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HCV-infected clinical study population [1]
In total, 16 subjects received treatment with Daclatasvir/BMS-790052 and two subjects received placebo. Subjects selected for this study included men and women aged 18–49 years, inclusive, who were chronically infected with HCV genotype 1 and were treatment naive or treatment non-responders, defined as subjects who received the current standard of care (interferon and/or ribavirin) and who continued to have a detectable HCV RNA level (including relapsers) or subjects who did not attain a 2 log10 decline in HCV RNA levels at 12 weeks and stopped treatment; or treatment-intolerant subjects, defined as subjects who were unable to tolerate the toxicities associated with interferon and/or ribavirin; and who had not received another NS5A replication co-factor inhibitor; and who were not co-infected with human immunodeficiency virus, hepatitis B virus or HCV other than genotype 1.

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30 mg/kg; oral

Mice

Absorption, Distribution and Excretion
Studies demonstrated that peak plasma concentrations typically occurred within 2 hours after administration of multiple oral doses ranging from 1 - 100 mg once daily. Steady state is reached after approximately 4 days of once-daily daclatasvir administration. The absolute bioavailability of the tablet formulation is 67%.
Approximately 88% of total dose of daclatasvir is eliminated into bile and feces in which 53% remains as unchanged form, while 6.6% of the total dose is eliminated primarily unchanged in the urine.
The approximate volume of distribution of daclatasvir is 47 L in patients who was orally administered 60 mg tablet followed by 100 µg [13C,15N]-daclatasvir intravenously.
In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg radiolabeled daclatasvir intravenously, the total clearance was 4.2 L/h.

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Metabolism / Metabolites
Daclastavir is a substrate of CYP3A enzymes where its metabolism is predominantly mediated by CYP3A4 isoform. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. High proportion of the drug in the plasma (greater than 97%) is in the unchanged form.

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Biological Half-Life
Following multiple dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours.

Hepatotoxicity
In large randomized controlled trials, daclatasvir was not associated with serum enzyme elevations during therapy. A difficulty in assessing side effects of daclatasvir and other anti-HCV agents, however, was that they are never used as monotherapy, but were also combined with agents active against other HCV targets, such as the viral protease (NS3) or polymerase (NS5B). Daclatasvir was also commonly used in combination with the more traditional agents used for hepatitis C, such as peginterferon and ribavirin, both of which have prominent adverse effects. In combination with asunaprevir (an HCV protease inhibitor), daclatasvir was associated with serum ALT elevations in 3% to 11% of patients and with several instances of acute hypersensitivity and hepatitis, some of which were severe. The cause of the hypersensitivity reaction, however, appeared to be asunaprevir. In combination with sofosbuvir, daclatasvir was not associated with serum enzyme elevations or with clinically apparent liver injury.
Daclatasvir has, however, been implicated in rare instances of acute decompensation of HCV related cirrhosis. The role of daclatasvir and the other HCV antivirals in this syndrome, however, was unclear. The liver injury usually arose within 2 to 6 weeks of starting therapy, but occasionally later and even after discontinuation of therapy. The injury was marked by worsening jaundice and signs of hepatic failure. In some instances, lactic acidosis was present early. In most but not all instances, the serum enzymes increased minimally if at all, despite the worsening hepatic failure. Several instances resulted in death or need for emergency liver transplantation. For this reason, it was recommended that patients with cirrhosis undergoing antiviral therapy with potent direct acting agents should be monitored carefully, particularly during the first few weeks of treatment.
Finally, reactivation of hepatitis B has occurred in rare patients being treated for chronic hepatitis C some of whom had received daclatasvir. The relationship of HBV reactivation to the antiviral treatment of HCV infection is not clear, but it may be due to clearance of HCV replication which allows HBV DNA levels to increase.
Likelihood score: C (probable rare cause of clinically apparent liver injury in patients with cirrhosis or preexisting hepatitis B virus coinfection).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Daclatasvir has been removed from the US market. It has not been studied in nursing mothers being treated for hepatitis C infection. Because it is 99% bound to maternal plasma proteins, amounts in breastmilk are likely to be very low. If daclatasvir used alone or in combination with sofosbuvir is required by the mother, it is not a reason to discontinue breastfeeding. Some sources recommend against breastfeeding when daclatasvir is used with ribavirin.
Hepatitis C is not transmitted through breastmilk and breastmilk has been shown to inactivate hepatitis C virus (HCV). However, the Centers for Disease Control recommends that mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. It is not clear if this warning would apply to mothers who are being treated for hepatitis C.
Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Daclatasvir is highly protein bound (99%).

[1]. Nature . 2010 May 6;465(7294):96-100.

[2]. Virology . 2011 May 25;414(1):10-8.

[3]. Antimicrob Agents Chemother . 2012 Mar;56(3):1588-90.

[4]. Antimicrob Agents Chemother . 2005 Apr;49(4):1346-53.

Pharmacodynamics
Daclatasvir is a direct-acting antiviral agent that targets the NS5A and causes a decrease in serum HCV RNA levels. It disrupts HCV replication by specifically inhibiting the critical functions of an NS5A protein in the replication complex. It is shown to cause downregulation of the hyperphosphorylation of NS5A. It does not appear to prolong the QT interval even when given at 3 times the maximum recommended dose.

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The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors. [1]

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The hepatitis C virus (HCV) non-structural (NS) 5A protein plays an essential role in the replication of the viral RNA by the membrane-associated replication complex (RC). Recently, a putative NS5A inhibitor, BMS-790052, exhibited the highest potency of any known anti-HCV compound in inhibiting HCV replication in vitro and showed a promising clinical effect in HCV-infected patients. The precise mechanism of action for this new class of potential anti-HCV therapeutics, however, is still unclear. In order to gain further insight into its mode of action, we sought to test the hypothesis that the antiviral effect of BMS-790052 might be mediated by interfering with the functional assembly of the HCV RC. We observed that BMS-790052 indeed altered the subcellular localization and biochemical fractionation of NS5A. Taken together, our data suggest that NS5A inhibitors such as BMS-790052 can suppress viral genome replication by altering the proper localization of NS5A into functional RCs.[2]

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The antiviral profile of BMS-790052, a potent hepatitis C virus (HCV) replication complex inhibitor targeting nonstructural protein NS5A, is well characterized for HCV genotype-1. Here, we report that BMS-790052 inhibits hybrid replicons containing HCV genotype-4 NS5A genes with 50% effective concentrations (EC(50)s) ranging from 7 to 13 pM. NS5A residue 30 was an important site for BMS-790052-selected resistance in the hybrid replicons. Our results support the potential of BMS-790052 as a valuable component of combination therapy for HCV genotype-4 chronic infection.[3]

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Daclatasvir is a member of the class of biphenyls that is a potent inhibitor of nonstructural protein 5A and is used (as its hydrochloride salt) for treatment of hepatitis C. It has a role as a nonstructural protein 5A inhibitor and an antiviral drug. It is a member of biphenyls, a member of imidazoles, a carbamate ester, a carboxamide and a valine derivative. It is a conjugate base of a daclatasvir(2+).
Daclatasvir is a direct-acting antiviral agent against Hepatitis C Virus (HCV) used for the treatment of chronic HCV genotype 1 and 3 infection. It is marketed under the name DAKLINZA and is contained in daily oral tablets as the hydrochloride salt form . Hepatitis C is an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients. Daclatasvir was the first drug with demonstrated safety and therapeutic efficacy in treating HCV genotype 3 without the need for co-administration of interferon or [DB00811]. It exerts its antiviral action by preventing RNA replication and virion assembly via binding to NS5A, a nonstructural phosphoprotein encoded by HCV. Binding to the N-terminus of the D1 domain of NS5A prevents its interaction with host cell proteins and membranes required for virion replication complex assembly. Daclatasvir is shown to target both the cis- and trans-acting functions of NS5A and disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status. The most common critical NS5A amino acid substitutions that led to reduced susceptibility to daclatasvir therapy occured at position Q30 (Q30H/K/R) and M28 in genotype 1a patients and Y93H in genotype 3 patients. According to 2017 American Association for the Study of Liver Diseases (AASLD), 60mg of daclatasvir is recommended with 400mg [DB08934] for genotype 1a/b patients with or without cirrhosis as second-line therapy. The same dosing regimen can be used as first-line therapy in patients with genotype 3 without cirrhosis and second-line therapy in genotype 3 patients with compensated cirrhosis. Combination therapies that include daclatasir can be used for challenging-to-treat patients who have HIV-1 coinfection, advanced cirrhosis, or post-liver transplant recurrence of HCV. The therapy is intended to cure or achieve a sustained virologic response (SVR12), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality. Daclatasvir was FDA-approved in July 2015 for use with [DB08934] (Sovaldi) with or without [DB00811] to treat HCV genotype 1 and 3 infections. The SVR12 in HCV genotype 1a-infected treatment-naïve subjects without and with cirrhosis undergoing daclatasvir and [DB08934] therapy were 88% and 99%, respectively. The same dosing regimen in treatment-naïve patients with HCV genotype 3 infection with or without cirrhosis achieved SVR12 rates of 71% and 98%, respectively.

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Daclatasvir is a Hepatitis C Virus NS5A Inhibitor. The mechanism of action of daclatasvir is as a P-Glycoprotein Inhibitor, and Organic Anion Transporting Polypeptide 1B1 Inhibitor, and Organic Anion Transporting Polypeptide 1B3 Inhibitor, and Breast Cancer Resistance Protein Inhibitor.
Daclatasvir is an orally available antiviral agent that inhibits the NS5A region of the hepatitis C virus (HCV) and was used in combination with other oral antiviral agents to treat chronic hepatitis C before its withdrawal in 2019. Elevations in serum enzyme levels during daclatasvir therapy are uncommon, and it has yet to be convincingly implicated in cases of idiosyncratic liver injury with jaundice. Nevertheless, successful all-oral regimens of antiviral therapy in patients with chronic hepatitis C and cirrhosis is occasionally complicated by hepatic decompensation and may cause reactivation of hepatitis B in susceptible patients coinfected with the hepatitis B virus (HBV).
Daclatasvir is an orally available inhibitor of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) replication complex, with potential activity against HCV. Although the exact mechanism of action of daclatasvir has yet to be fully determined, this agent, upon oral administration and after intracellular uptake, appears to bind to domain I of the NS5A protein. This inhibits the activity of the NS5A protein and results in the disruption of the viral RNA replication complex, blockage of viral HCV RNA production, and inhibition of viral replication. NS5A, a zinc-binding and proline-rich hydrophilic phosphoprotein, plays a crucial role in HCV RNA replication. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family.
DACLATASVIR is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2014 and is indicated for viral disease and chronic hepatitis c virus infection and has 7 investigational indications. This drug has a black box warning from the FDA.

C40H50N8O6

738.890

738.385

C, 65.02; H, 6.82; N, 15.17; O, 12.99

1009119-64-5

Daclatasvir dihydrochloride;1009119-65-6;Daclatasvir-d6;1801709-41-0;Daclatasvir-d16

25154714

Light yellow to yellow solid powder

1.3±0.1 g/cm3

1071.2±65.0 °C at 760 mmHg

601.7±34.3 °C

0.0±0.3 mmHg at 25°C

1.595

5.44

174.64

4

8

13

54

1190

4

O=C([C@@H](NC(OC)=O)C(C)C)N1CCC[C@H]1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C5=CN=C([C@@H]6CCCN6C([C@@H](NC(OC)=O)C(C)C)=O)N5)C=C4

FKRSSPOQAMALKA-CUPIEXAXSA-N

InChI=1S/C40H50N8O6/c1-23(2)33(45-39(51)53-5)37(49)47-19-7-9-31(47)35-41-21-29(43-35)27-15-11-25(12-16-27)26-13-17-28(18-14-26)30-22-42-36(44-30)32-10-8-20-48(32)38(50)34(24(3)4)46-40(52)54-6/h11-18,21-24,31-34H,7-10,19-20H2,1-6H3,(H,41,43)(H,42,44)(H,45,51)(H,46,52)/t31-,32-,33-,34-/m0/s1

methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate dihydrochloride

BMS-790052; Daclatasvir; BMS790052; Daclatasvir; 1009119-64-5; BMS-790,052; BMS790,052; EBP 883; Daclatasvir [USAN]; BMS 790,052; methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate; BMS 790052; EBP883; EBP 883; EBP-883; BMS 790052; Daclatasvir [USAN];Daklinza (trade name)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 (3.38 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 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；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 2 中的溶解度: ≥ 2.5 mg/mL (3.38 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 25.0 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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配方 3 中的溶解度: ≥ 2.5 mg/mL (3.38 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。