HCV 1a (EC50 = 4 nM); HCV 1b (EC50 = 3 nM); HCV 2a (EC50 = 3 nM)

Elbasvir exhibits strong activity against the 1a and 1b genotype replicons, as evidenced by its EC90 of 0.006 nM for the 1a_H77 wild-type and 1b_con1 replicons. With an EC90 of 0.12 nM, elasvir inhibits genotype 3 replicons. The decreases in colony counts at higher doses of elbasvir (0.06 nM, 0.6 nM, and 6 nM) show dose-dependent suppression of resistant genotype 1a replicons. With EC50s in the low-picomolar range, elbasvir exhibits high potency against HCV replicons carrying NS5A sequences from GT1a, -1b, -2a(31L), -3a, -4a, -5a, and -6.

Phase 1b clinical trial results. (i) Subject accounting.[1]
A total of 48 patients received Elbasvir or placebo in an elbasvir dose-ranging study, including 17 patients with genotype 1a, 13 patients with genotype 1b, and 18 with genotype 3. All patients completed the 5-day course of therapy. Mislabeling of 7 samples from 3 patients (1 each infected with genotype 1a, 1b, or 3) occurred at the sequencing facility; these samples were therefore excluded from the analysis. Baseline virus from 1 additional genotype 3 patient could not be amplified. Consequently, only sequence data from the other 44 patients (including 16 with genotype 1a, 12 with genotype 1b, and 16 with genotype 3) were used for the resistance analyses.

Variants with NS5A substitutions at positions 28, 30, 58, and 93 (which had been previously identified as potential RAVs for NS5A inhibitors) were detected at baseline in 7 of 44 patients (15.9%) (Table 6). Except for possibly 1 patient infected with genotype 3 in the 10-mg Elbasvir dose group, baseline NS5A variants did not appear to impact the magnitude of viral load reduction during treatment. In particular, M28V or Q30R in genotype 1a and Y93H in genotype 1b at baseline had little impact on the magnitude of viral load reduction during treatment.

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(ii) Genotype 1 infections.[1]
All doses of Elbasvir led to rapid HCV RNA reductions of 3.7 to 5.1 log10 IU/ml in genotype 1 infections. At the same dose, larger viral load reductions were achieved in genotype 1b infections than in infections with genotype 1a. The viral load decline after discontinuation of 5-day elbasvir monotherapy was more sustained in genotype 1b patients than in genotype 1a patients at the same elbasvir dose. In general, the types and prevalence of postbaseline RAVs selected within each subgenotype were similar across dosing levels.

In the 2 genotype 1a patients with pretreatment M28V or Q30R polymorphisms, >3-log viral load reductions were achieved with 5 mg and 50 mg dosing of Elbasvir, respectively. In the patient with baseline M28V (which did not confer elbasvir resistance in vitro) treated with the 5-mg dose of elbasvir, Q30H/Q and L31L/V were additionally detected during the posttreatment follow-up period along with M128V/A. Clonal analysis identified linkages between M28Vand L31V as well as between M28A and Q30H, but no linkage was found between L31V and Q30H. Only M28V was detectable at the last follow-up on day 61 by population sequencing. In the genotype 1a patient with baseline Q30R (associated with a 24-fold increase in elbasvir EC90 in vitro) treated with the 50-mg dose of elbasvir, Q30R was detected with L31V from the end of treatment until the last follow-up on day 56. Clonal sequencing was not performed for this patient. One genotype 1b patient with Y93H/Y and A92T/A mixtures at baseline treated with the 50-mg dose of elbasvir achieved a >4-log viral load reduction (even though Y93H was associated with a 67-fold increase in elbasvir EC90 in vitro). After treatment cessation, clonal sequencing identified L28M linked to Y93H and L31V linked to A92K, without linkage between Y93H and either L31V or A92K. At the last visit on day 59, only the Y93H/Y and L31V/L mixtures were detected by population sequencing.

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(iii) Genotype 3 infections.[1]
Antiviral responses were less robust for genotype 3 than for genotype 1 infections in the 10-mg Elbasvir dosing group, but mean HCV RNA reductions of ∼3 log were achieved at the 50- and 100-mg doses (3). Posttreatment Y93H was found in all 10 patients in the 50- and 100-mg elbasvir dose groups and persisted through the last follow-up in each case. L31F was also detected in 2 of these patients.

One of the 3 evaluated patients with genotype 3 infection in the 10-mg dose group harbored a baseline A30A/E/K/T mixture and had a <1-log10 IU/ml reduction in the level of HCV RNA at nadir compared to a mean 1.43-log10 drop in viremia in the other 2 patients in the 10-mg dosing group without detectable RAVs at baseline. Population sequencing showed that A30A/E/K/T converted to A30K (which conferred a 41-fold increase in Elbasvir EC90 in vitro) from treatment discontinuation through the last follow-up on day 61.

Elbasvir is an HCV NS5A inhibitor that, depending on genotype, has a median EC50 value ranging from 0.2 to 3600 pmol/L. It inhibits the replication of the hepatitis C virus and the assembly of virion.

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HCV replicons were used to determine the effective concentrations (EC) of Elbasvir necessary to inhibit HCV RNA levels by a specified percentage (50% or 90%) for genotypes 1a, 1b, and 3 variants compared to no treatment. Replicons maintained in 0.5 mg/ml of G418 to select replicating cells were seeded on 384-well plates in Dulbecco's modified Eagle medium (DMEM) containing 5% fetal calf serum. Twofold dilutions of elbasvir concentrations from 1 μM down to 0.002 μM were added to the medium the next day in the presence of 0.5% dimethyl sulfoxide (DMSO). After 72 h of incubation, cells were harvested and subjected to real-time reverse transcriptase PCR (RT-PCR). For each variant, threshold cycle numbers were plotted against the log of elbasvir concentrations and fitted to a sigmoid dose-response curve using Prism to obtain the EC50 and EC90 (the drug concentrations needed to achieve 50% and 90% inhibition, respectively, relative to a DMSO control without drug). For reference, the steady-state minimum concentration (Cmin) for once-daily 50 mg elbasvir dosing is about 22 nM [1].

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Kinetic analysis of the combination of grazoprevir and Elbasvir in GT1a. [2]
The “independent-effects” definition of additive response was used to assess the nature of inhibitor interactions (synergistic, additive, or antagonistic). Inhibitor interactions were analyzed with the aid of MacSynergy software, which requires input data in linear scale. To fulfill that requirement the log-scale measurements of threshold cycle number (CT) were converted into relative amounts of RNA using the standard curves from the same assay plate. The standard curves were constructed with total RNA isolated from replicon cells and then serially diluted. The relative amount of replicon RNA from each sample (treated cells in each well) was calculated based on the CT of the sample and the standard curve from the same plate. MacSynergy calculates an additive response at each combination and defines synergy as a response that exceeds additivity and antagonism as a response that is less than additivity. The application then calculates synergy/antagonism volumes at a ≥95% confidence interval and categorizes the results as synergy, additivity, or antagonism.

To select cell lines with decreased Elbasvir susceptibility, subconfluent monolayers of replicon cells were cultured in the presence of various drug concentrations at multiples of EC90. Plates were prepared at 2 × 105 cells per 60-mm plate and passaged only once at a 1:10 ratio when the cells reached 95% confluence. Colonies surviving selection were first counted and then pooled and expanded for analysis. The colony count in the presence of elbasvir was divided by the number of cells seeded to calculate resistance frequency. Total cellular RNA was isolated from pooled colonies and amplified by RT-PCR. The RT-PCR products were purified with a QIAquick PCR purification kit, and the full-length NS5A gene was sequenced. Additionally, the RT-PCR products were cloned into the TOPO TA vector, and the plasmid DNA from bacterial colonies was sequenced to look for linked variations. The replicative capacity (“fitness”) of RAVs was evaluated in a replicon colony formation assay [1].

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Stable-replicon assay. [2]
Stable-replicon cell lines were tested for compound sensitivity. Briefly, replicon cells were seeded in 384-well plates in Dulbecco modified Eagle medium (DMEM) containing 0.5 mg/ml G-418. Concentrations spanning the 50% effective concentration (EC50) for each compound were used independently or in the combination studies for grazoprevir and Elbasvir. The compounds were serially diluted individually in 100% dimethyl sulfoxide (DMSO) and then were added to the medium in the presence of 5% fetal calf serum (FCS) with cells in 1:200 dilutions on the day after cells were seeded. The final DMSO concentration was 0.5% (vol/vol). After 72 h of incubation, cells were harvested and subjected to real-time PCR analysis as reported previously. The primer/probe sets used for the PCR analysis on an ABI Prism 7900HTS sequence detection system are listed in Table S2 in the supplemental material. The independent and combination studies were tested 3 times with triplicate plates in each experiment (or run).

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Long-term viral kinetic studies. [2]
Stable-replicon cells were seeded in 6-well plates at various cell concentrations for confluence at harvest and then dosed 6 h later at 1× EC90 with grazoprevir and Elbasvir independently for a final DMSO concentration of 0.5% (vol/vol) in DMEM containing 10% fetal bovine serum (FBS) without G418. Treated cells were harvested with trypsin-EDTA (0.25%) at 0, 24, 48, 72, 96, 168, 240, and 336 h (with cell passing at 72, 168, and 240 h), and RNA was isolated utilizing the RNeasy purification kit via the manufacturers protocol. RNA was then subjected to real-time PCR analysis as reported previously using the above-mentioned primers and probes. The threshold cycle numbers (CT) were normalized to the GAPDH (glyceraldehyde-3-phosphate dehydrogenase) housekeeping gene to yield ΔCT, and the log(1/power) (2,ΔCT − average ΔCT of DMSO at day zero) was plotted over time using Prism.

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Compound treatment to select for emergence of resistance. [2]
GT1a subgenomic replicon cells were seeded onto multiple 6-cm tissue culture dishes at a density of 2 × 105 cells/dish. Four dishes were prepared for each treatment condition. Twenty-four hours after plating, cells were dosed with various combinations and multiples of the EC90 values of grazoprevir and Elbasvir (as indicated in appropriate tables and figures). Media and compounds were refreshed twice a week. In the event that the monolayer reached confluence (e.g., with the DMSO treatment control), those cells were passaged at a 1:10 ratio. At about 3 to 4 weeks postinitiation, when resistant replicon cells formed defined colonies, 3 of the 4 dishes were fixed and stained with a crystal violet solution for colony counting. Cells on the remaining dish were expanded for further analysis (i.e., sequencing of reverse transcription-PCR [RT-PCR] products and phenotypic sensitivity to compounds).

Phase 1b randomized clinical trial design. [1]
MK-8742 P002 was a randomized, double-blind, placebo-controlled, sequential dose-escalating phase 1b study of Elbasvir monotherapy to assess safety, pharmacokinetics, and viral responses in adult men with chronic HCV-1 or HCV-3 infection. Patients between 18 and 60 years of age (up to 65 years old at the discretion of the investigator) with HCV RNA levels of >100,000 IU/ml were eligible. Elbasvir doses were 5, 10, and 50 mg once daily for patients infected with genotype 1a or 1b, and 10, 50, and 100 mg once daily for patients infected with genotype 3. A total of 6 patients were to be enrolled at each dosing level, including 5 patients to receive elbasvir and 1 patient to receive a matching placebo orally for 5 consecutive days, starting at the lowest dose for the infecting genotype. Doses were escalated stepwise once adequate safety data had been reviewed from the previous dosing group. Viral load and resistance testing was to be performed daily and every other day, respectively, for the first 10 days of the study and then at 2 weeks, 3 weeks, 1 month, and 2 months after the last dose of elbasvir. The study was conducted in accordance with good clinical practice guidelines. All participants provided written informed consent.

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Viral quantification, sequencing, and resistance analyses. [1]
In the phase 1b study, HCV RNA levels were measured in plasma specimens obtained at baseline, during and at the end of Elbasvir monotherapy, and at periodic follow-up visits by the TaqMan 2.0 assay with lower limits of quantification and detection of 25 and 9.3 IU/ml, respectively. Blood samples were also collected for viral resistance testing at prespecified time points, including prior to the first elbasvir dose, near the nadir of the HCV RNA level, and up to 2 months after the last elbasvir dose provided that the HCV RNA level remained >1,000 IU/ml. [1]
The full-length NS5A gene was amplified from plasma samples using RT-PCR followed by population and selective clonal sequencing. Due to the sensitivity of the assay, resistance analyses were routinely performed only on samples with HCV RNA levels of >1,000 IU/ml. The resultant amino acid sequences were compared to genotype 1a (H77; GenBank no. NC_004102), genotype 1b (con1; GenBank no. AJ238799), or genotype 3 (S52; GenBank no. GU814263) referents. The limit of variant detection in population sequencing was presumed to be ∼20 to 25% of the viral quasispecies. Polymorphisms identified in ≥10% of patients were selected for more detailed analysis. For clonal sequencing, amino acids 1 to 448 of NS5A were amplified by RT-PCR, and the resultant amplicons were cloned into a TOPO TA vector. Approximately 40 clones were sequenced at each time point. Polymorphisms detected in more than a single clone were included in the analysis. [1]
In phenotypic analyses to determine the antiviral potency of Elbasvir against detected variants, genotype-specific replicons were constructed to incorporate NS5A polymorphisms. The shift (n-fold) in elbasvir EC for each variant replicon was expressed relative to the EC for the corresponding wild-type replicon. The fitness of resistant variants was evaluated by comparing colony counts to a wild-type referent.

Absorption, Distribution and Excretion
Elbavir reaches peak plasma concentrations 3–6 hours after administration, with an absolute bioavailability of 32%. Peak concentrations increase 1.5-fold with food, but this increase in exposure is unlikely to be clinically significant. Elbavir is primarily excreted in feces (90%), with very little excretion in urine (<1%). The apparent volume of distribution of elbavir is estimated at 680 liters. It is believed to be distributed in most tissues, including the liver. The clearance of elbavir has not been determined. Metabolism/Metabolites Elbavir is partially eliminated via CYP3A-mediated oxidative metabolism. Circulating metabolites of elbavir have not been detected in human plasma. Biological Half-Life In HCV-infected individuals, the geometric mean apparent terminal half-life of elbavir is 24 hours.

Effects During Pregnancy and Lactation
◉ Summary of Medication Use During Lactation
Studies on elbasvir in breastfeeding women undergoing treatment for hepatitis C have not been conducted. Because it binds to maternal plasma proteins at a rate exceeding 99.9%, its concentration in breast milk is likely to be very low. Some sources suggest that breastfeeding should be avoided when elbasvir 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 U.S. Centers for Disease Control and Prevention (CDC) recommends that breastfeeding should be considered if the mother has cracked or bleeding nipples. It is unclear whether this warning applies to mothers undergoing treatment for hepatitis C.
Infants born to HCV-infected mothers should be tested for HCV infection; 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.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Elbasvir binds to plasma proteins at a rate exceeding 99.9%. It binds to human serum albumin and α1-acid glycoprotein.

[1]. Susceptibilities of genotype 1a, 1b, and 3 hepatitis C virus variants to the NS5A inhibitor Elbasvir. Antimicrob Agents Chemother. 2015 Nov;59(11):6922-6929.

[2]. The Combination of Grazoprevir, a Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor, and Elbasvir, an HCV NS5A Inhibitor, Demonstrates a High Genetic Barrier to Resistance in HCV Genotype 1a Replicons. Antimicrob Agents Chemother. 2016 A.

Pharmacodynamics
Elbasvir belongs to the direct-acting antiviral (DAA) class and inhibits viral replication of HCV genotypes 1a, 1b, and 4. Elbasvir is a complex organic heterotetracyclic compound and an inhibitor of the hepatitis C virus nonstructural protein 5A. It is used in combination with grazoprevir (trade name: zapartil) to treat chronic HCV genotype 1 or 4 infection in adults. It has a dual role as an antiviral agent, a hepatoprotective agent, and an inhibitor of the hepatitis C virus nonstructural protein 5A. It is an L-valine derivative and belongs to the imidazole class, carbamate class, N-acylpyrrolidine class, organic heterotetracyclic class, and cyclic class of compounds. Elbasvir is a direct-acting antiviral drug used in combination therapy for chronic hepatitis C. Chronic hepatitis C is an infectious liver disease caused by hepatitis C virus (HCV) infection. 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 patients with chronic hepatitis C. Since 2011, significant progress has been made in treatment options for chronic hepatitis C with the development of direct-acting antiviral agents (DAAs) such as elbasvir. Elbasvir is an NS5A inhibitor; the NS5A protein is essential for viral replication and viral particle assembly. The resistance barrier to NS5A inhibitors is lower than that of NS5B inhibitors (another class of direct-acting antiviral agents). Mutations at amino acid positions 28, 30, 31, or 93 are known to lead to resistance to elbasvir. Despite this drawback, elbasvir remains effective against hepatitis C virus (HCV), especially when used in combination with grazoprevir. Elbasvir and grazoprevir (trade name: Zepatier) are marketed as a fixed-dose combination product for the treatment of chronic hepatitis C. Zepatier was approved by the FDA in January 2016 for the treatment of HCV genotypes 1 and 4. Its use in combination with ribavirin can be chosen based on the presence of resistance-related amino acid substitutions in the NS5A protein and failure to respond to previous treatment with ribavirin, pegylated interferon alpha-2a, pegylated interferon alpha-2b, or other NS3/4A inhibitors (such as boceprevir, simeprevir, or telaprevir). Elbavir and grazoprevir can be used in combination with or without ribavirin, with the aim of achieving a cure or sustained virological response (SVR). Studies have shown that after 12 weeks of treatment, the SVR rate in genotype 1 HCV-infected patients can reach 94% to 97%, and the SVR rate in genotype 4-infected patients can reach 97% to 100%. Eradication of SVR and hepatitis C virus 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. A computer-based drug retargeting study published in April 2020 predicted that elbasvir could stably and preferentially bind to three proteins required for SARS-CoV-2 (the human coronavirus that caused the COVID-19 pandemic) viral replication. While these results suggest antiviral efficacy, further clinical trials are needed to validate elbasvir's effectiveness as a potential treatment for SARS-CoV-2. Elbasvir is a hepatitis C virus NS5A inhibitor. Its mechanism of action is as an inhibitor of breast cancer resistance proteins. Elbasvir is a small molecule drug, with clinical trials up to Phase IV (covering all indications), first approved in 2016 for viral diseases and chronic hepatitis C virus infection, and has two investigational indications. Elbasvir is an investigational NS5A inhibitor that has shown activity against multiple HCV genotypes in vitro. Its antiviral activity was determined in replicons derived from wild-type or resistant variants of genotypes 1a, 1b, and 3. The resistance barrier was assessed by the number of resistant colonies screened after exposure to different concentrations of elbasvir. In a phase 1b dose-escalation study, 48 non-cirrhotic adult men with chronic genotype 1 or 3 infection were randomized to either placebo or elbasvir at a dose of 5 to 50 mg (genotype 1) or 10 to 100 mg (genotype 3) once daily for 5 days. The NS5A gene was sequenced in plasma samples collected before, during, and after treatment. Elbasvir inhibited the emergence of resistance-associated variants (RAVs) in vitro in a dose-dependent manner. Variants selected after exposure to high concentrations of elbasvir typically encode multiple amino acid substitutions (most commonly at sites 30, 31, and 93), conferring high elbasvir resistance. In monotherapy studies, HCV RNA levels decreased more significantly in patients with genotype 1b than in those with genotype 1a at all doses of elbasvir; efficacy was generally less significant in patients with genotype 3 than in those with genotype 1, especially at lower doses of elbasvir. The major resistance-associated variants (RAVs) for genotype 1a were M28T, Q30R, L31V, and Y93H; for genotype 1b, L31V and Y93H; and for genotype 3, A30K, L31F, and Y93H. Patient virological outcomes were consistent with preclinical observations. In laboratory studies and clinical trials, NS5A-RAV most frequently occurred at amino acid sites 28, 30, 31, and 93. (The MK-8742 P002 trial is registered on ClinicalTrials.gov with registration number NCT01532973.) [1]

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When patients with chronic hepatitis C virus (HCV) infection are treated with a single drug, the choice of drug resistance-associated variants (RAVs) makes it necessary to develop direct-acting antiviral agents (DAAs) that target multiple viral proteins to overcome treatment failure caused by drug resistance. Therefore, this study investigated the combination of NS3/4A protease inhibitor grazozopvir (formerly known as MK-5172) and NS5A inhibitor elbasvir (formerly known as MK-8742) in genotype 1a (GT1a) replicon cells. Both compounds showed extremely high activity in GT1a wild-type replicon cells, with 90% effective concentrations (EC90) values of 0.9 nM and 0.006 nM for grazozopvir and elbasvir, respectively. Resistance analysis of clinically significant NS5A and NS3 resistance-associated variants (RAVs) using grazoprevir and elbasvir separately revealed no cross-resistance. Kinetic analysis of HCV RNA levels over 14 days showed that grazoprevir and elbasvir inhibited typical NS5A Y93H and NS3 R155K RAVs, respectively, with kinetic characteristics similar to those observed in wild-type GT1a replicon cells. The combination of grazoprevir and elbasvir exhibited an additive effect in GT1a replicon cells. Colony formation assays using a grazoprevir-elbasvir combination inhibitor at a concentration 10-fold higher than the EC90 value inhibited the emergence of resistance colonies compared to grazoprevir or elbasvir inhibitors alone. Resistance-associated variants (RAVs) carried by resistance colonies selected through combination therapy required changes in two or more nucleotides in the codon. Homologous gene mutations resulted in a greater loss of potency with elbasvir than with grazoprevir. The reduced adaptability of RAV-carrying replicons identified from drug-resistant colonies to various cell lines may contribute to the activity of this combination therapy. These studies show that the combination of grazoprevir and elbasvir has a potent inhibitory effect on HCV RNA replication and a high genetic resistance barrier. The combination of grazoprevir and elbasvir is currently approved for the treatment of chronic hepatitis C virus (HCV) infection. [2] Elbasvir in combination with grazoprevir (an investigational NS3/4A protease inhibitor) in a once-daily oral single-dose combination tablet is currently under development for the treatment of chronic HCV infection. Further analysis of the phase 3 clinical trial of grazoprevir-elbasvir will soon provide more key data on the safety and efficacy of this novel dual direct-acting antiviral combination. [1] Overall, these results indicate that the combination of the NS3/4A inhibitor grazoprevir and the NS5A inhibitor elbasvir effectively inhibits HCV RNA synthesis without antagonism and has a high genetic resistance barrier. This combination of inhibitors offers an attractive oral, interferon-free direct-acting antiviral alternative for patients with chronic HCV infection. In recent clinical studies, in vitro activity translated into significant clinical efficacy for this combination therapy. In treatment-naïve patients with GT1a hepatitis C virus infection, sustained virological response (SVR) was achieved in 95% of patients taking 50 mg/100 mg elbasvir/grazoprevir once daily. The resistance-associated variants (RAVs) and major resistance pathways observed in clinical studies of patients with GT1a hepatitis C virus infection were largely consistent with in vitro findings. The most common post-treatment NS5A resistance-associated variant in virological failure cases was located at the Q30 site. Similarly, the D168 amino acid substitution was the most common post-treatment NS3 resistance-associated variant in virological failure cases. This combination therapy was approved in January 2016 for the treatment of chronic hepatitis C virus infection. [2]

C49H55N9O7

882.02

881.422

C, 66.72; H, 6.29; N, 14.29; O, 12.70

1370468-36-2

71661251

White to yellow solid powder

1.4±0.1 g/cm3

1.701

6.98

4

9

13

65

1680

5

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])C1([H])C1=NC([H])=C(C2C([H])=C([H])C3=C(C=2[H])C([H])=C2C4C([H])=C([H])C(=C([H])C=4O[C@@]([H])(C4C([H])=C([H])C([H])=C([H])C=4[H])N23)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]

BVAZQCUMNICBAQ-PZHYSIFUSA-N

InChI=1S/C49H55N9O7/c1-27(2)41(54-48(61)63-5)45(59)56-20-10-14-37(56)43-50-25-34(52-43)30-17-19-36-32(22-30)23-39-33-18-16-31(24-40(33)65-47(58(36)39)29-12-8-7-9-13-29)35-26-51-44(53-35)38-15-11-21-57(38)46(60)42(28(3)4)55-49(62)64-6/h7-9,12-13,16-19,22-28,37-38,41-42,47H,10-11,14-15,20-21H2,1-6H3,(H,50,52)(H,51,53)(H,54,61)(H,55,62)/t37-,38-,41-,42-,47-/m0/s1

methyl N-[(2S)-1-[(2S)-2-[5-[(6S)-3-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]-6-phenyl-6H-indolo[1,2-c][1,3]benzoxazin-10-yl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

Elbasvir; Zepatier; MK8742; MK 8742; Elbasvir; 1370468-36-2; Elbasvir [USAN]; Elbasvir [USAN:INN]; UNII-632L571YDK; 632L571YDK; MK-8742

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 (2.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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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 (Please use freshly prepared in vivo formulations for optimal results.)