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 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.

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.

[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 a hydrochloride obtained by combining daclatasvir with two molar equivalents of hydrochloric acid. It is a potent inhibitor of nonstructural protein 5A and is used for treatment of hepatitis C. It has a role as an antiviral drug and a nonstructural protein 5A inhibitor. It contains a daclatasvir(2+).
Daclatasvir Dihydrochloride is the dihydrochloride salt form of daclatasvir, 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.

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Drug Indication
Daklinza is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections 4. 2, 4. 4 and 5. 1).

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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.

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.)