HCV replicon genotype 1a (EC50 = 50 pM); HCV replicon genotype 1b (EC50 = 9 pM); HCV replicon genotype 2a (EC50 = 71 pM); HCV replicon genotype 3a (EC50 = 146 pM); HCV replicon genotype 5a (EC50 = 33 pM); HCV replicon genotype 4a (EC50 = 12 pM); NS5A33-202 (Kd = 8 nM); NS5A26-202 (Kd = 210 nM); OATP1B (IC50 = 1.5 µM); OATP1B3 (IC50 = 3.27 µM)

Daclatasvir (BMS-790052) shows significant inhibitory activity against every genotype examined, with EC50 values spanning from 9 pM to 146 pM. With an EC50 of 50 pM, 9 pM, 71 pM, 146 pM, 12 pM, and 33 pM, respectively, daclatasvir inhibits HCV replicon genotypes 1a, 1b, 2a, 3a, 4a, and 5a. EC50=28 pM, the infectious virus that causes JFH-1 genotype 2a to replicate in cell culture, is effectively inhibited by daclatasvir[1]. The binding constants of daclatasvir (BMS-790052) are 8 nM and 210 nM, respectively, for NS5A33-202 and NS5A26-202[2].

Daclatasvir (BMS-790052; 30 mg/kg; oral administration; daily; for 27 days) treatment rapidly lowers serum HCV RNA titers by about 1.5 log10 on day 3[4].

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In a randomized, double-blind, placebo-controlled, single ascending-dose study, Daclatasvir/BMS-790052 was administered at six dose levels to healthy, non-HCV-infected subjects over a range of 1 to 200 mg as an oral solution. The compound was safe and well tolerated up to 200 mg with no clinically relevant adverse effects. After oral administration, BMS-790052 was readily absorbed, with dose-proportional exposures over the studied dose range, and all subjects had drug concentrations greater than the protein-binding-adjusted EC90 for genotypes 1a and 1b, as measured in the replicon assay, at and beyond 24 h post-dose (Fig. 3). (The protein binding-adjusted EC90 figures were derived from an analysis of the effect of the addition of human serum on antiviral activity in replicons. In the presence of 40% human serum, the EC90 for BMS-790052 is 383 pM (0.28 ng ml-1) for the genotype 1a replicon and 49 pM (0.04 ng ml-1) for the genotyope 1b replicon.) [1]

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In a randomized, double-blind, placebo-controlled, single ascending-dose study, Daclatasvir/BMS-790052 was administered to subjects with genotype 1 chronic HCV at doses of 1, 10 and 100 mg as an oral solution. All subjects were infected with HCV genotype 1a except for two subjects at 10 mg and three subjects at 100 mg who were infected with genotype 1b. BMS-790052 was safe and well tolerated in HCV-infected subjects after single oral doses up to 100 mg. Specifically, there were no deaths, serious adverse events, discontinuations due to adverse events or clinically relevant adverse effects. Headache was the most frequent adverse event, reported by four subjects after administration of BMS-790052. In HCV-infected subjects, BMS-790052 had a mean plasma elimination half-life ranging from 10 to 14 h, and plasma drug levels were similar to those in non-HCV-infected subjects. After single oral doses of 10–100 mg BMS-790052, all subjects had 24-h plasma concentrations above the tenfold protein binding-adjusted EC90 for HCV genotypes 1a and 1b, suggesting the possibility for once daily administration. The plasma HCV RNA levels were measured for up to 6 days after administration; the mean decline from the time of administration to 144 h post-dose is shown in Fig. 4. A single milligram dose of BMS-790052 produced a mean 1.8 log10 reduction (range 0.2–3.0 log10) in HCV viral load measured 24 h after drug administration. Both the 10 and 100 mg doses produced a greater antiviral effect, with mean plasma viral RNA falling by 3.2 log10 (range 2.9–4.0 log10) and 3.3 log10 (range 2.7–3.6 log10), respectively, at 24 h post-dose. Moreover, the 100 mg dose resulted in a mean maximal HCV RNA decline of 3.6 log10 (range 3.0–4.1 log10) and a prolonged antiviral response was observed in two subjects infected with genotype 1b virus, with an HCV RNA measurement that reached the lower limit of quantification (less than 25 IU ml-1) in one subject and 35 IU ml-1 in the other measured at hour 144. Genotypic analysis of samples taken at baseline (T0), 24 (T24) and 144 (T144) hours post-dose revealed that, in general, a marked reduction in viral load was required to detect major HCV variants. Substitutions were observed at amino-acid positions identified using the in vitro replicon system (Supplementary Tables 12–14): M28T, Q30H/R and L31M for genotype 1a, and Y93H for genotype 1b, results that suggest the usefulness of the replicon system for assessing resistance in response to inhibitor pressure in vivo. Follow-up samples were available for only one of these subjects, which revealed that HCV RNA had returned to near baseline; however, genotype analysis was not performed on this sample. As would be anticipated based on the in vitro replicon potency of BMS-790052, a greater and more sustained decline in HCV RNA was observed for subjects infected with genotype 1b (mean 3.6 log10 reduction (range 3.1–4.0 log10) and mean 3.1 log10 reduction (range 2.7–3.4 log10) in HCV viral load measured 24 h after a 10 and 100 mg dose, respectively) than for subjects infected with genotype 1a (mean 1.8 log10 reduction (range 0.2–3.0 log10), mean 2.9 log10 reduction (range 2.9–3.0 log10) and mean 3.6 log10 reduction (range 3.5–3.6 log10) in HCV viral load measured 24 h after a 1, 10 and 100 mg dose, respectively). The mean rates of decline for subjects who received 10 and 100 mg doses of BMS-790052 were similar up to 36 h after dosing, after which the mean decline was greater and more sustained in the subjects who received 100 mg. Subjects who received 1 mg of BMS-790052 had a lower mean decline in HCV RNA than subjects treated with 10 and 100 mg (Fig. 4). However, multiple-dose studies are needed to define the optimal dose range for maximal antiviral effect beyond the first phase of viral decline. The relationships between maximum decline from baseline in HCV RNA and drug pharmacokinetics exposures were explored using Pearson’s correlation coefficients. All estimated Pearson’s correlation coefficients were above 0.65, suggesting that the maximum declines in log10 HCV RNA and log pharmacokinetics exposures (BMS-790052 Cmax, AUC(0-T), AUC(INF), C12 and C24) were positively correlated; that is, that the maximum declines in log10 HCV RNA increase with the exposure to Daclatasvir/BMS-790052[1].

Solution MST binding studies were performed using standard protocols on a Monolith NT.115. Briefly, recombinant NS5A26–202, NS5A33–202, L31V NS5A26–202, Y93H NS5A33–202 or control protein was labelled using the RED-NHS (Amine Reactive) Protein Labelling Kit. NS5A was mixed with either RNA, Daclatasvir (BMS790052) or AZD7295 with a final buffer condition of 25 mM Tris-HCl, pH 8.0, containing 250 mM NaCl, 10% glycerol, 0.05% Tween-20 and 5% DMSO. Each replicate contained a 16 step 2- to 4-fold serial dilution series. The protein concentration (12 nM) was chosen such that the observed fluorescence was approximately 1000 units at 40% LED power. The samples were loaded into hydrophobic capillaries and heated at 40% laser power for 30 sec, followed by 5 sec cooling. The data were normalised against the baseline obtained in the absence of any inhibitor, and the maximal response obtained at the highest concentration of inhibitor. The dissociation constant KD was obtained by plotting the normalised fluorescence Fnorm against the logarithm of the different concentrations of the dilution series resulting in a sigmoidal binding curve that could be directly fitted with a non-linear solution of the law of mass action. All experiments were performed with a minimum of 3 replicates and the normalised fluorescence temperature jump curves were analysed using GraphPad Prism. KD's were compared by one-way Anova with Tukey posttest and p < 0.01 was considered to be statistically significant. A Hill slope analysis suggested 1 inhibitor molecule binds per NS5A dimer. No measurable interactions with several unrelated proteins including insulin-regulate membrane aminopeptidase, nicastrin and carbonic anhydrase were observed by MST for either compound. In another control we added excess EDTA to NS5A33–202 to remove metal from the Zn2+ binding site (leading to destabilisation of the protein fold) and no binding to RNA or either compound was observed.[2]

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Daclatasvir is a potent inhibitor of the HCV NS5A protein, with mean EC50 values against the genotype 1a and 1b replicons of 50 and 9 pM, respectively.

NS5A coding region or the first 100 amino acids of NS5A from different genotypes were substituted for the corresponding sequence of the parent replicon in hybrids created with replication-competent 1a or 1b replicons to test daclatasvir's antiviral activity towards genotypes. Half-maximum effective concentrations (EC50) for daclatasvir ranged from 9 to 146 pM, indicating that it is highly potent against all HCV genotypes.

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Transporter inhibition assays (preincubation method).[3]
Based on the method described in a previous report (15), the 1B1/HEK, 1B3/HEK, or mock/HEK cells were preincubated with a DAA for 30 min at 0.1, 1.0, and 10 μM, after which the cells were washed twice with inhibitor-free transport assay buffer (Krebs-Henseleint buffer [KHB]). Immediately, assays of E2G or CCK-8 uptake by the cells were performed in inhibitor-free KHB, as described above. CsA, which is known to have preincubation inhibition effects on the OATP1B1/1B3 function, was used as a control in any experiments relevant to the preincubation inhibition effect.

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Transporter inhibition assays (long-lasting preincubation method). [3]
The long-lasting preincubation inhibition effects of DAAs on OATP1Bs were examined using a similar method to that described above. The cells were preincubated with a DAA for 30 min at 1.0 μM, after which they were washed once with inhibitor-free DMEM. Immediately thereafter, the cells were washed with KHB and then subjected to E2G or CCK-8 uptake assays, as described above, or they were further incubated with inhibitor-free DMEM in 5% CO2 at 37°C. After 1 or 3 h of additional incubation, the cells were washed with KHB, and the OATP1B functions were assessed by the transport assay.

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Transporter inhibition assays (pre- and coincubation combination method). [3]
The cells were preincubated with DMSO (0.1%) or a DAA at concentrations of 0.1, 0.4, and 1.0 μM as described in the preincubation method, immediately after which the OATP1B functions were determined in the presence of a DAA at the same concentration used in preincubation.

NOD/SCID male mice (5 weeks of age, 18-20 g) bearing HCV RNA-transfected cells[4]
30 mg/kg
Oral administration; daily; for 27 days

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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.[4]

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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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Absorption, Distribution and Excretion
Studies have shown that peak plasma concentrations typically occur within 2 hours after a once-daily oral dose of 1–100 mg. Steady-state is reached approximately 4 days after once-daily administration of daclatasvir. The absolute bioavailability of the tablet formulation is 67%. Approximately 88% of the total dose of daclatasvir is excreted in bile and feces, with 53% excreted unchanged and 6.6% primarily excreted unchanged in urine. In patients who received an oral 60 mg tablet followed by an intravenous injection of 100 µg of [13C,15N]-daclatasvir, the volume of distribution of daclatasvir was approximately 47 L. In subjects who received an oral 60 mg daclatasvir tablet followed by an intravenous injection of 100 µg of radiolabeled daclatasvir, the total clearance was 4.2 L/h.

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Metabolism/Metabolites
Daclatasvir is a substrate of the CYP3A enzyme, and its metabolism is primarily mediated by the CYP3A4 isoenzyme. The oxidative pathway involves the δ-oxidation of the pyrrolidine moiety, leading to ring opening to form an aminoaldehyde intermediate, followed by an intramolecular reaction of the aldehyde with the adjacent imidazole nitrogen atom. The majority (greater than 97%) of the drug in plasma exists unchanged.

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Biological Half-Life
In HCV-infected patients, after multiple doses of daclatasvir (dosage range of 1 mg to 100 mg once daily), the terminal elimination half-life of daclatasvir is approximately 12 to 15 hours.

Effects During Pregnancy and Lactation
◉ Overview of Breastfeeding Use
Daclatasvir has been withdrawn from the US market. No studies have been conducted on breastfeeding women receiving treatment for hepatitis C virus infection. Due to its high binding rate (up to 99%) to maternal plasma proteins, its concentration in breast milk may be very low. Breastfeeding does not need to be discontinued if the mother requires daclatasvir alone or in combination with sofosbuvir. Some sources suggest that breastfeeding should be avoided when daclatasvir is used in combination with ribavirin.
Hepatitis C is not transmitted through breast milk, and breast milk has been shown to inactivate the hepatitis C virus (HCV). However, the US Centers for Disease Control and Prevention (CDC) recommends that breastfeeding should be considered if an HCV-infected mother experiences nipple fissures or bleeding. It is currently unclear whether this warning applies to mothers receiving treatment for hepatitis C. Infants born to mothers infected with hepatitis C virus (HCV) should be tested for HCV; nucleic acid testing is recommended because maternal antibodies persist for the first 18 months of life and before the infant develops an immune response. ◉ Impact on breastfed infants: No published information found as of the revision date. ◉ Impact on breastfeeding and breast milk: No published information found as of the revision date.

[1]. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010 May 6;465(7294):96-100.

[2]. Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Sci Rep. 2014 Apr 23;4:4765.

[3]. Different interaction profiles of direct-acting anti-hepatitis C virus agents with human organic anion transporting polypeptides. Antimicrob Agents Chemother. 2014 Aug;58(8):4555-64.

[4]. HA1077 displays synergistic activity with daclatasvir against hepatitis C virus and suppresses the emergence of NS5A resistance-associated substitutions in mice. Sci Rep. 2018 Aug 20;8(1):12469.

Daclatasvir hydrochloride is the hydrochloride form of daclatasvir prepared by reacting it with two molar equivalents of hydrochloric acid. It is a potent non-structural protein 5A inhibitor used to treat hepatitis C. It is both an antiviral drug and a non-structural protein 5A inhibitor. It contains daclatasvir (2+). Daclatasvir dihydrochloride is the dihydrochloride form of daclatasvir and is an orally effective inhibitor of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) replication complex, possessing potential anti-HCV activity. Although the exact mechanism of action of daclatasvir is not fully elucidated, after oral administration and intracellular absorption, it appears to bind to domain I of the NS5A protein. This inhibits the activity of the NS5A protein, leading to the disruption of the viral RNA replication complex, blocking HCV RNA production, and inhibiting viral replication. NS5A is a proline-rich, zinc-binding, hydrophilic phosphoprotein that plays a crucial role in HCV RNA replication. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family. Drug Indications Daclatasvir (Daklinza), used in combination with other drugs, is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults (see Sections 4.2, 4.4, and 5.1). Pharmacodynamics Daclatasvir is a direct-acting antiviral drug that targets NS5A and reduces serum HCV RNA levels. It disrupts HCV replication by specifically inhibiting the key function of the NS5A protein in the replication complex. Studies have shown that the drug downregulates NS5A hyperphosphorylation. Even at doses up to three times the maximum recommended dose, it does not appear to prolong the QT interval. It is estimated that there are nearly 200 million people infected with chronic hepatitis C virus (HCV) worldwide. Current treatment is pegylated interferon-alpha in combination with ribavirin, but this regimen is poorly tolerated, and sustained virological response rates in patients infected with HCV type 1 are typically less than 50%. The development of direct-acting antiviral agents for the treatment of HCV has primarily focused on inhibitors of the viral enzyme NS3 protease and RNA-dependent RNA polymerase NS5B. This article describes the characteristics of BMS-790052, a small-molecule inhibitor of the HCV NS5A protein that exhibits picomolar-level half-maximal effective concentrations (EC50) against replicons expressing multiple HCV genotypes and against JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients with chronic HCV infection, a single administration of 100 mg BMS-790052 resulted in a 3.3 log10 reduction in mean viral load at 24 hours, and this inhibitory effect lasted for 120 hours in two patients infected with genotype 1b virus. Genotypic analysis of samples collected at baseline, 24 hours, and 144 hours post-administration revealed substitutions at amino acid sites identified in the in vitro replicon system in the observed major HCV variants. These results are the first clinical validation of HCV NS5A inhibitors (a protein whose enzyme function is currently unknown) as a strategy to inhibit viral replication and are expected to become part of a treatment regimen based on HCV inhibitor combination therapy. [1] The non-structural protein (NS) 5A of hepatitis C virus (HCV) plays a crucial role in the process of viral RNA replication mediated by the membrane-associated replication complex (RC). Recently, a suspected NS5A inhibitor, BMS-790052, has shown the highest known efficacy among anti-HCV compounds in inhibiting HCV replication in vitro and has shown good clinical efficacy in HCV-infected patients. However, the exact mechanism of action of this new potential anti-HCV drug remains unclear. In order to further understand its mechanism of action, we attempted to verify whether the antiviral effect of BMS-790052 may be achieved by interfering with the functional assembly of HCV RC. We observed that BMS-790052 did indeed alter the subcellular localization and biochemical composition of NS5A. In summary, our data suggest that NS5A inhibitors, such as BMS-790052, can inhibit viral genome replication by altering the proper localization of NS5A in the functional replication complex (RC). [2]

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BMS-790052 is a potent hepatitis C virus (HCV) replication complex inhibitor that targets the non-structural protein NS5A, whose antiviral properties have been well characterized in HCV genotype 1. Here, we report that BMS-790052 has inhibitory effects on heterozygous replicons containing the HCV genotype 4 NS5A gene, with half-maximal effective concentrations (EC50) ranging from 7 to 13 pM. NS5A residue 30 is an important site of selective resistance to BMS-790052 in heterozygous replicons. Our results support the potential of BMS-790052 as an important component of combination therapy for chronic HCV genotype 4 infection. [3] Daclatasvir belongs to the biphenyl class of compounds and is a potent inhibitor of nonstructural protein 5A (in its hydrochloride form) used to treat hepatitis C. It is both a nonstructural protein 5A inhibitor and an antiviral drug. It belongs to the biphenyl, imidazole, carbamate, carboxamide, and valine derivative classes. It is the conjugate base of daclatasvir (2+). Daclatasvir is an antiviral drug that acts directly on the hepatitis C virus (HCV) and is used to treat chronic HCV genotypes 1 and 3. It is marketed under the brand name DAKLINZA and is available in daily oral tablets in the form of hydrochloride. Hepatitis C is an infectious liver disease caused by infection with the hepatitis C virus (HCV). HCV is a single-stranded RNA virus with nine different genotypes, of which genotype 1 is the most common in the United States, accounting for 72% of all chronic HCV patients. Daclatasvir was the first drug proven to be safe and effective for treating HCV genotype 3 without the need for combination therapy with interferon or [DB00811]. It exerts its antiviral effect by binding to the HCV-encoded non-structural phosphoprotein NS5A, inhibiting RNA replication and viral particle assembly. Binding to the N-terminus of the NS5A D1 domain prevents its interactions with host cell proteins and membranes, interactions essential for the assembly of the viral particle replication complex. Daclatasvir targets both cis and trans-acting functions of NS5A and disrupts the function of the novel HCV replication complex by modulating the phosphorylation state of NS5A. The most common key NS5A amino acid substitutions leading to decreased daclatasvir treatment sensitivity occur at the Q30 site (Q30H/K/R) and M28 site in genotype 1a patients, and at the Y93H site in genotype 3 patients. Based on the 2017 recommendations of the American Association for the Study of Liver Diseases (AASLD), 60 mg daclatasvir in combination with 400 mg [DB08934] is recommended as a second-line treatment regimen for genotype 1a/b patients with or without cirrhosis. For genotype 3 patients without cirrhosis, this dosing regimen can be used as a first-line treatment; for genotype 3 patients with compensated cirrhosis, this regimen can be used as a second-line treatment. For treatment-refractory patients with HIV-1 infection, advanced cirrhosis, or HCV relapse after liver transplantation, combination therapy containing daclatasvir can be used. This therapy aims to cure HCV infection or achieve sustained virological response (SVR12), which can be achieved after 12 weeks of daily treatment. Eradication of SVR and 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 approved by the FDA in July 2015 for use in combination with [DB08934] (sofosbuvir) or alone with [DB00811] for the treatment of HCV genotypes 1 and 3 infection. In treatment-naïve patients with HCV genotype 1a infection treated with daclatasvir and [DB08934], the SVR12 rates were 88% and 99%, respectively, regardless of cirrhosis. In treatment-naïve patients with HCV genotype 3 infection treated with the same regimen, the SVR12 rates were 71% and 98%, respectively, regardless of cirrhosis. Daclatasvir is a hepatitis C virus NS5A inhibitor. Its mechanism of action is as a P-glycoprotein inhibitor, an organic anion transporter peptide 1B1 inhibitor, an organic anion transporter peptide 1B3 inhibitor, and a breast cancer resistance protein inhibitor. Daclatasvir is an oral antiviral drug that inhibits the NS5A region of hepatitis C virus (HCV). Before its withdrawal from the market in 2019, it was used in combination with other oral antiviral drugs to treat chronic hepatitis C. Elevated serum enzyme levels during daclatasvir treatment are uncommon, and there is currently no conclusive evidence that they are associated with specific liver injury cases with jaundice. However, in patients with chronic hepatitis C and cirrhosis, even with an all-oral antiviral regimen, liver decompensation can sometimes occur, potentially leading to hepatitis B virus reactivation in susceptible patients (co-infected with hepatitis B virus (HBV)). Daclatasvir is an oral inhibitor of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) replication complex and has potential anti-HCV activity. Although the exact mechanism of action of daclatasvir is not fully elucidated, after oral administration and intracellular absorption, it appears to bind to domain I of the NS5A protein. This inhibits NS5A protein activity, leading to the disruption of the viral RNA replication complex, blocking HCV RNA production, and thus inhibiting viral replication. NS5A is a proline-rich, zinc-binding, hydrophilic phosphoprotein that plays a crucial role in HCV RNA replication. Hepatitis C virus (HCV) is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family. Daclatasvir (DACLATASVIR) is a small molecule drug that has completed Phase IV clinical trials (covering all indications) and was first approved in 2014 for the treatment of viral diseases and chronic hepatitis C virus infection. It also has seven investigational indications. The drug has been placed on the U.S. Food and Drug Administration's (FDA) black box warning list.

C40H52N8CL2O6

738.88

810.338

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

1009119-65-6

Daclatasvir;1009119-64-5

25154713

White to off-white solid powder

8.11

6

8

13

56

1190

4

O=C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C(=O)OC([H])([H])[H])N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C1=NC([H])=C(C2C([H])=C([H])C(=C([H])C=2[H])C2C([H])=C([H])C(=C([H])C=2[H])C2=C([H])N=C([C@]3([H])C([H])([H])C([H])([H])C([H])([H])N3C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C(=O)OC([H])([H])[H])=O)N2[H])N1[H]

BVZLLUDATICXCI-JMSCDMLISA-N

InChI=1S/C40H50N8O6.2ClH/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);2*1H/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; BMS 790052; EBP 883;EBP-883; EBP883; BMS790052; Daclatasvir 2HCl; Daclatasvir HCl; EBP-883; Daclatasvir 2HCl; Daklinza; Daclatasvir (dihydrochloride); Daclatasvir dihydrochloride; 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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 1 mg/mL (1.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1 mg/mL (1.23 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1 mg/mL (1.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)