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Purity: ≥98%
Daclatasvir dihydrochloride (BMS790052; EBP883; BMS-790052; EBP-883; Daklinza), the dihydrochloride salt of Daclatasvir, is a novel, highly potent and selective HCV NS5A protease inhibitor that has been approved in 2014 in EU for use in combination with sofosbuvir for the treatment of hepatitis C (HCV) by causing a decrease in serum HCV RNA levels. With an EC50 of 9–50 pM, it inhibits the HCV NS5A protease.
| Targets |
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)
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| ln Vitro |
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].
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| ln Vivo |
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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| Enzyme Assay |
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]
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. |
| Cell Assay |
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.
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. 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. 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. |
| Animal Protocol |
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 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] |
| Toxicity/Toxicokinetics |
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. |
| References |
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| Additional Infomation |
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. 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). , , For HCV genotype specific activity, see sections 4. 4 and 5. 1. , |
| Molecular Formula |
C40H52N8CL2O6
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| Molecular Weight |
738.88
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| Exact Mass |
810.338
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| Elemental Analysis |
C, 65.02; H, 6.82; N, 15.17; O, 12.99
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| CAS # |
1009119-65-6
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| Related CAS # |
Daclatasvir;1009119-64-5
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| PubChem CID |
25154713
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| Appearance |
White to off-white solid powder
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| LogP |
8.11
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
56
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| Complexity |
1190
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| Defined Atom Stereocenter Count |
4
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| SMILES |
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]
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| InChi Key |
BVZLLUDATICXCI-JMSCDMLISA-N
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| InChi Code |
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
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| Chemical Name |
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
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| Synonyms |
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)
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| HS Tariff Code |
2934.99.9001
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| Storage |
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. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. View More
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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3534 mL | 6.7670 mL | 13.5340 mL | |
| 5 mM | 0.2707 mL | 1.3534 mL | 2.7068 mL | |
| 10 mM | 0.1353 mL | 0.6767 mL | 1.3534 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03748745 | Completed | Drug: Daclatasvir dihydrochloride Drug: SH229 |
Drug Interactions | Nanjing Sanhome Pharmaceutical, Co., Ltd. |
November 19, 2018 | Phase 1 |
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