HCV NS5A (EC50 = 9 pM-50 pM)

BMS-790052 is among the strongest HCV replication inhibitors found to date. For HCV genotype 1a and 1b replicons, the mean EC50 values of BMS-790052 are 50 and 9 pM, respectively. BMS-790052 is inactive against a panel of 10 RNA and DNA viruses, with an EC50 greater than 10 μM, and exhibits a therapeutic index (CC50/EC50) of at least 10⁵. This validates the HCV specificity of BMS-790052.[1] BMS-790052, with EC50 values ranging from 1 to 15 pM, inhibits both transient and stable HCV genome replication in Huh7 cells expressing the HCV genotype 1b replicons. It has been demonstrated that BMS-790052 (100 pM or 1 nM) modifies the subcellular localization and biochemical fractionation of NS5A.[2] With an EC50 of 7–13 pM, BMS-790052 suppresses hybrid replicons carrying HCV genotype–4 NS5A genes. In the hybrid replicons, residue 30 of NS5A plays a crucial role in BMS-790052-mediated resistance.[3]

Humanized liver chimeric mice, with an estimated 40% chimeric liver, receive intravenous injections of 100 µL of human serum samples positive for HCV. Every one to four weeks following the vaccination, their blood is drawn from an external jugular vein. With a lower measurement range of 3.2 log IU/mL serum, the COBAS TaqMan HCV test measures the HCV RNA levels in 100-fold diluted serum. Once serum HCV RNA levels plateau, mice are given 40 mg/kg of Asunaprevir plus 30 mg/kg of Daclatasvir, 15 mg/kg of Ledipasvir plus 50 mg/kg of GS-558093, or 50 mg/kg of GS-558093 plus 400 mg/kg of Telaprevir orally once a day for four weeks.

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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].

The peptide (Ac-Asp-Glu-Asp [EDANS]-Glu-Glu-Abu-[COO] Ala-Ser-Lys [DABCYL]-NH2) contains a fluorescence donor {EDANS, 5-[(2-aminoethyl)amino]naphthalene-1-sulfonic acid} near one end of the peptide and an acceptor {DABCYL, 4-[(4-dimethylamino)phenyl]azo)benzoic acid} near the other end. Intermolecular resonance energy transfer between the donor and the acceptor quenches the fluorescence of the peptide, but as the NS3 protease cleaves the peptide, the products are released from resonance energy transfer quenching. The fluorescence of the donor increases over time as more substrate is cleaved by the NS3 protease. The assay reagent consists of 20 μM FRET peptide, 150 mM NaCl, and 5× luciferase cell culture lysis reagent diluted to 1× with dH₂O. In a 96-well plate, HCV-Huh-7 cells are added and left to attach for the entire night (1×10⁴ cells per well). The plate is incubated for 72 hours after BMS-790052 is added to the wells the following day. After that, the plate is cleaned with PBS and prepared for the FRET test by adding 30 μL of the previously mentioned FRET peptide assay reagent to each well. Signals are acquired by reading the plate in the kinetic mode with the Cytofluor 4000 instrument, which is programmed to operate in the automatic mode at 340 nm (excitation)/490 nm (emission) for 20 cycles or less. Once FRET is completed, each well is filled with 40 μL of luciferase substrate, and the amount of luciferase is evaluated.

BMS-790052 is added to 96-well plates that have HCV replicon cells seeded in 200 µL media about 12 hours earlier.After being incubated for 72 hours, the cell plates are examined for cytotoxicity and replication activity. Following the measurement of cytotoxicity using CellTiter-Blue, the media and dye are removed, the plates are inverted, and the liquid that remains is blotted with paper towels. Renilla luciferase is used to measure the HCV genotype 1a cell lines' replication activity. After adding 1× Renilla luciferase lysis buffer (30 µL) to each well, the plates are incubated for 15 minutes with light shaking. The signals are then detected using a Top Count luminometer that is configured for light emission quantification after adding 40 µL of renilla luciferase substrate. The DMSO-only wells calculate 100% activity for each cell line; the average value for compound-containing wells is divided by the average value for DMSO-containing wells to determine the percentage activity for each inhibitor concentration.

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 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.

Hepatotoxicity
In large randomized controlled trials, no elevation of serum enzymes was observed during daclatasvir treatment. However, the challenge in assessing the side effects of daclatasvir and other anti-HCV drugs lies in the fact that they are never used alone, but are usually used in combination with other drugs targeting other HCV targets, such as viral protease (NS3) or polymerase (NS5B). Daclatasvir is also frequently used in combination with traditional drugs for treating hepatitis C, such as pegylated interferon and ribavirin, both of which have significant adverse effects. When used in combination with asunavir (an HCV protease inhibitor), daclatasvir caused elevated serum ALT in 3% to 11% of patients, with several cases of acute hypersensitivity and hepatitis, some of which were severe. However, the cause of the hypersensitivity appears to be asunavir. When used in combination with sofosbuvir, daclatasvir did not cause elevated serum enzymes or clinically significant liver damage. However, daclatasvir has been associated with rare cases of acute decompensated hepatitis C virus (HCV)-related cirrhosis. However, the role of daclatasvir and other HCV antiviral drugs in this syndrome remains unclear. Liver injury typically occurs within 2 to 6 weeks of starting treatment, but occasionally it can occur after treatment or even after discontinuation of the drug. Liver injury is characterized by worsening jaundice and signs of liver failure. In some cases, lactic acidosis may occur early. Despite worsening liver failure, serum enzyme elevations are minimal or absent in most (but not all) cases. Some cases ultimately lead to death or require emergency liver transplantation. Therefore, close monitoring of cirrhotic patients receiving potent direct-acting antiviral therapy is recommended, especially in the initial weeks of treatment. Finally, in a small number of patients receiving treatment for chronic hepatitis C, hepatitis B virus (HBV) reactivation has occurred, some of whom had previously received daclatasvir. The relationship between HBV reactivation and antiviral treatment for HCV infection is unclear, but it may be related to elevated HBV DNA levels resulting from HCV replication clearance.
Probability Score: C (Possibly a rare cause of clinically significant liver damage in patients with cirrhosis or a history of hepatitis B virus infection).

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Impact of Pregnancy and Lactation
◉ Overview of Use During Lactation
Daclatasvir has been withdrawn from the US market. Studies have not been conducted in breastfeeding women receiving treatment for hepatitis C. Because daclatasvir binds to maternal plasma proteins in up to 99%, its concentration in breast milk may be very low. This is not a reason to discontinue breastfeeding 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 unclear whether this warning applies to mothers receiving treatment for hepatitis C. Infants born to mothers infected with HCV should be tested for HCV; nucleic acid testing is recommended because maternal antibodies are present in the infant for the first 18 months after birth 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.

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Protein binding
Daclatasvir has a high protein binding rate (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 drug that targets NS5A and reduces serum HCV RNA levels. It blocks HCV replication by specifically inhibiting the key function of the NS5A protein in the replication complex. Studies have shown that it downregulates NS5A hyperphosphorylation. Even when administered at three times the maximum recommended dose, it does not appear to prolong the QT interval. It is estimated that nearly 200 million people worldwide are infected with chronic hepatitis C virus (HCV). Current treatment relies on the combination of pegylated interferon-alpha and ribavirin, a regimen that is poorly tolerated, with sustained virological response rates typically below 50% in genotype 1 infected individuals. Development of direct-acting antiviral drugs against hepatitis C virus (HCV) has primarily focused on inhibitors of the viral enzyme NS3 protease and RNA-dependent RNA polymerase NS5B. This article describes the properties of BMS-790052, a small-molecule inhibitor of the HCV NS5A protein, which 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. Genotyping analysis of samples collected at baseline, 24 hours, and 144 hours post-dose revealed substitutions at amino acid sites identified in the in vitro replicon system for the observed major HCV variants. These results provide the first clinical validation, from a clinical perspective, of HCV NS5A inhibitors (proteins whose enzymatic function is currently unknown) as a strategy for inhibiting viral replication and hold promise as part of HCV inhibitor-based combination therapy regimens. [1] Hepatitis C virus (HCV) nonstructural protein (NS) 5A plays a crucial role in membrane-associated replication complex (RC)-mediated viral RNA replication. Recently, a putative NS5A inhibitor, BMS-790052, has demonstrated the highest known efficacy among anti-HCV compounds in inhibiting HCV replication in vitro and has shown promising clinical efficacy in HCV-infected patients. However, the exact mechanism of action of this novel potential anti-HCV therapy remains unclear. To further understand its mechanism of action, we sought to verify whether the antiviral effect of BMS-790052 might be mediated by interfering with the functional assembly of the HCV replication complex (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 within the functional 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, and its antiviral properties have been well characterized in HCV genotype 1. This paper reports that BMS-790052 can inhibit heterozygous replicons containing the HCV genotype 4 NS5A gene, with an average effective concentration (EC50) of 7 to 13 pM. NS5A residue 30 is an important site for BMS-790052 to select for resistance 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 the non-structural protein 5A. Its hydrochloride salt is used to treat hepatitis C. It is both a non-structural protein 5A inhibitor and an antiviral drug. It belongs to the biphenyl, imidazole, carbamate, carboxamide, and valine derivative classes. It is a conjugate 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 infection. 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, affecting 72% of chronic HCV patients. Daclatasvir was the first drug proven to be safe and effective in treating HCV genotype 3 without the need for combination therapy with interferon or [DB00811]. Daclatasvir exerts its antiviral effect by binding to the non-structural phosphoprotein NS5A encoded by the hepatitis C virus (HCV), inhibiting RNA replication and viral particle assembly. Daclatasvir binds to the N-terminus of the NS5A D1 domain, preventing its interactions with host cell proteins and membranes, interactions essential for the assembly of the viral particle replication complex. Studies have shown that daclatasvir can target both cis and trans-acting functions of NS5A and disrupt 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 susceptibility occur at the Q30 site (Q30H/K/R) and M28 site in genotype 1a patients, and at the Y93H site in genotype 3 patients. According to the 2017 recommendations of the American Association for the Study of Liver Diseases (AASLD), 60 mg daclatasvir in combination with 400 mg hepatitis C virus (DB08934) is recommended as a second-line treatment for genotype 1a/b hepatitis C virus infection, regardless of cirrhosis. The same dosage regimen can be used as first-line treatment for patients infected with genotype 3 hepatitis C virus (HCV) without cirrhosis, and as second-line treatment for patients infected with genotype 3 HCV with compensated cirrhosis. For treatment-refractory patients with concurrent HIV-1 infection, advanced cirrhosis, or HCV relapse after liver transplantation, combination therapy containing daclatasvir can be used. The goal of this therapy is cure or sustained virological response (SVR12) after 12 weeks of daily treatment. Sustained virological response (SVR) and eradication of hepatitis C virus (HCV) infection are 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 HCV genotype 1a patients receiving combination therapy with daclatasvir and [DB08934], the SVR12 rates were 88% and 99%, respectively, regardless of cirrhosis. In treatment-naïve HCV genotype 3 patients receiving the same dosing 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.

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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.38 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.5 mg/mL (3.38 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 25.0 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: ≥ 2.5 mg/mL (3.38 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 25.0 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.)