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Purity: ≥98%
GSK-2336805 (also known as GSK-805; GSK2336805; JNJ-56914845) is a novel and potent inhibitor of HCV NS5A. It has the potential for the treatment of HCV infection. Nonstructural protein 5A (NS5A) is an essential component of the HCV replication complex. The NS5a protein interacts with other key viral products (NS4B, NS5B, RNA) and host cell proteins (cyclophilin A, kinases, etc.) to regulate viral replication and assembly. GSK2336805 retained activity on chimeric replicons containing NS5A patient sequences from genotype 1 and patient and consensus sequences for genotypes 4 and 5 and part of genotype 6. Combination and cross-resistance studies demonstrated that GSK2336805 could be used as a component of a multidrug HCV regimen either with the current standard of care or in combination with compounds with different mechanisms of action that are still progressing through clinical development.
GSK2336805 (also known as JNJ-56914845, GSK-805) is an orally bioavailable hepatitis C virus (HCV) inhibitor that works through an NS5A-mediated mechanism . It is a potent small-molecule inhibitor of HCV replication with multigenotype activity, developed for the treatment of chronic hepatitis C infection as part of combination therapy . The compound demonstrated preclinical activity on standard genotype 1a, 1b, and 2a subgenomic replicons at picomolar concentrations and retained activity on chimeric replicons containing NS5A patient sequences from genotypes 1, 4, 5, and part of genotype 6 . GSK2336805 was evaluated in Phase I and II clinical trials in combination with peginterferon, ribavirin, and other direct-acting antivirals .| Targets |
Hepatitis C Virus (HCV) Non-Structural Protein 5A (NS5A) [1].
GSK2336805 targets the hepatitis C virus non-structural protein 5A (NS5A), a multifunctional zinc-containing phosphoprotein essential for both viral RNA replication and the assembly of new virions . The compound acts via a viral NS5A-mediated mechanism, and resistance studies have identified changes in the N-terminal region of NS5A that cause decreased activity of GSK2336805 . Mutations in the genotype 1b replicon showed modest shifts in compound activity (less than 13-fold), while mutations identified in the genotype 1a replicon had a more dramatic impact on potency . |
|---|---|
| ln Vitro |
In stable HCV replicon assays, 41H showed potent activity against both genotype 1a (gt1a) and genotype 1b (gt1b), with pEC₅₀ values of 10.4 and 11.1, respectively [1].
In transient replicon assays with gt1b NS5A mutants, 41H maintained high potency. The pEC₅₀ values were 11.5 for the L28V mutant, 10.6 for the L31V mutant, and 10.6 for the Y93H mutant, compared to 11.1 for wild-type gt1b. This represented only a 3.2-fold reduction in EC₅₀ for the Y93H mutant, indicating a superior resistance profile [1]. In a 20-day HCV RNA reduction assay using gt1b replicon cells, 41H demonstrated a potent and sustained antiviral effect. At concentrations 3× and 10× the EC₉₀, 41H reduced HCV RNA levels by approximately 2 log₁₀ at day 5, and further to 3 log₁₀ and 4 log₁₀ by day 20, respectively. This reduction was 10-fold greater than that observed with daclatasvir at the 10× EC₉₀ concentration [1]. GSK2336805 is an inhibitor of HCV replication with picomolar activity on the standard genotype 1a, 1b, and 2a subgenomic replicons . The compound exhibited a modest serum shift and was not active on 22 RNA and DNA viruses that were profiled, indicating specificity for HCV . GSK2336805 retained activity on chimeric replicons containing NS5A patient sequences from genotype 1 and patient and consensus sequences for genotypes 4 and 5 and part of genotype 6 . The 50% effective concentration (EC50) values were determined using stable replicon cell lines expressing luciferase, with measurements taken 48 hours after dosing . The compound demonstrated no significant cytotoxicity in the cell lines tested . |
| ln Vivo |
In a clinical study, genotype 1 HCV-infected patients were given a single dose of up to 120 mg of 41H. The mean HCV RNA reduction from baseline ranged from 0.996 log₁₀ copies/mL for patients receiving a 1 mg dose to a mean reduction of 2.95 log₁₀ copies/mL after a single 120 mg dose [1].
In subjects chronically infected with HCV genotype 1, reductions in HCV RNA were observed within 4 hours of GSK2336805 administration, and a single dose of ≥10 mg resulted in a statistically significant ≥2-log reduction in HCV RNA compared with placebo at 24 hours post-dose . The compound was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing . In a Phase II study, GSK2336805 was co-administered with peginterferon alfa-2a and ribavirin through 4 weeks of treatment, and the number of participants achieving rapid virological response (RVR) at Day 28 was assessed as a primary outcome measure . Combination and cross-resistance studies demonstrated that GSK2336805 could be used as a component of a multidrug HCV regimen either with the current standard of care or with compounds with different mechanisms of action . |
| Enzyme Assay |
The preclinical characterization of the compound primarily utilized cell-based replicon assays rather than direct biochemical binding assays, given that NS5A is a multifunctional protein that functions within a multi-protein replication complex rather than having a traditional enzymatic active site . Resistance mutations were identified by site-directed mutagenesis using a QuikChange mutagenesis kit, and replicon variants carrying single point mutations were generated to assess the impact on compound activity .
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| Cell Assay |
Stable HCV Replicon Assay: Huh-luc/neo-ET replicon cells were seeded in 96-well plates and incubated overnight. Compounds were added as 10-point, 2-fold serial dilutions. After 48 hours of incubation, luciferase activity was measured to determine HCV RNA replication levels. Cytotoxicity was assessed in parallel using a WST-1 reagent. Data were analyzed using a four-parameter sigmoidal curve fit to calculate pEC₅₀ values [1].
Transient Replicon Mutant Assay: The method for this assay was referenced from another publication (ref 17 in the original paper) and was used to evaluate the potency of 41H against NS5A mutants L28V, L31V, and Y93H in gt1b [1]. 20-Day HCV RNA Reduction Assay: gt1b replicon cells were maintained in the presence of 41H at concentrations equivalent to 3× or 10× the calculated EC₉₀ for 20 days. HCV RNA levels were measured at various time points to assess the long-term antiviral effect. The same assay was performed with daclatasvir as a comparator [1]. Stable replicon cell lines carrying bicistronic genotype 1a (H77), genotype 1b (Con-1 ET with cell culture-adapted mutations), or genotype 2a (JFH-1) replicon expressing luciferase and neomycin phosphotransferase were used. Cells were seeded at a density of 2 × 10⁴ cells per well in 96-well assay plates containing compounds or DMSO in assay medium (DMEM supplemented with 5% FBS, penicillin-streptomycin, and nonessential amino acids), with a final volume of 200 μl. For 384-well assay plates, 5 × 10³ cells were added per well. Cells were incubated at 37°C with 5% CO₂. Plates were removed from the incubator at 48 hours after dosing, allowed to equilibrate to room temperature, and HCV replication was monitored by determining firefly luciferase activity using Steady-Glo, with luminescence measured in an EnVision 2103 multilabel reader. Cytotoxicity was measured on parallel plates using CellTiter-Glo. EC50 and CC50 values were calculated by curve fitting data to the Hill equation using a nonlinear least-squares curve-fitting program . |
| Animal Protocol |
No specific animal study protocols (e.g., dosing formulation, route, frequency) were described for 41H in the provided literature. However, pharmacokinetic data from rats, dogs, and cynomolgus monkeys are reported, indicating that in vivo studies were conducted [1].
The available literature focuses primarily on human clinical trials, including first-in-human studies in healthy subjects and HCV-infected patients , pharmacokinetic studies in subjects with hepatic impairment , and drug-drug interaction studies in healthy Japanese participants . Preclinical characterization of the compound was conducted using in vitro replicon systems rather than animal models . |
| ADME/Pharmacokinetics |
In Vivo Pharmacokinetics in Rats: In rats, 41H showed an in vivo clearance rate of approximately 60% of hepatic blood flow. Its oral bioavailability (F) was 13% [1].
In Vivo Pharmacokinetics in Dogs and Monkeys: In beagle dogs, 41H exhibited a clearance rate of 85% of hepatic blood flow and high oral bioavailability (F=85%). In cynomolgus monkeys, the clearance rate was 91% of hepatic blood flow [1]. Hepatocyte Stability: 41H was stable in hepatocytes from dogs, cynomolgus monkeys, and humans, with a half-life (t₁/₂) of ≥360 minutes in all three species. Consistent with its higher in vivo clearance in rats, it was less stable in rat hepatocytes, with a t₁/₂ of 160 minutes [1]. GSK2336805 is readily absorbed after oral administration, with a half-life (t1/2) suitable for once-daily dosing . Administration with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median tmax of 4.5 hours with food versus 2.0 hours in the fasted state . In healthy subjects, single doses of 10 mg, 30 mg, and 60 mg and multiple doses of 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) were evaluated . In HCV-infected subjects, single doses ranging from 1 to 120 mg were administered . In subjects with hepatic impairment (mild, moderate, and severe by Child-Pugh score), a single oral 60 mg dose resulted in plasma AUC₀₋∞ that was 26%, 52%, and 45% lower, respectively, relative to healthy subjects, with no difference in half-life among the groups. The apparent oral clearance and volume of distribution were higher in subjects with hepatic impairment, and lower plasma concentrations were largely explained by decreased plasma protein binding . The molecular weight of GSK2336805 is 796.91 g/mol, with molecular formula C₄₂H₅₂N₈O₈ . For research storage, the powder is stable for 3 years at -20°C, and in-solvent stocks are stable for 1 year at -80°C . |
| Toxicity/Toxicokinetics |
Cellular Toxicity: 41H was non-toxic in cellular assays up to a concentration of 40 μM [1].
Cytochrome P450 Inhibition: 41H did not inhibit cytochrome P450 enzymes 1A2, 2C9, 2D6, 2C19, and 3A4, with IC₅₀ values >33 μM for all tested isoforms [1]. Time-Dependent CYP3A4 Inhibition: 41H was inactive in a time-dependent CYP3A4 inhibition assay against the substrates midazolam, nifedipine, and atorvastatin, suggesting a low risk for drug-drug interactions [1]. Plasma Protein Binding: 41H was 94% bound to human serum albumin and 86% bound to human α1-acid glycoprotein (α1AGP) [1]. In clinical studies, GSK2336805 was generally well tolerated. In the first-in-human study, twenty subjects who received GSK2336805 experienced mild to moderate adverse events, with none being serious . In a Phase II study of GSK2336805 in combination with peginterferon and ribavirin, safety was assessed by monitoring adverse events, clinical laboratory tests (hematology, serum chemistry), electrocardiograms (QTcF interval), and vital signs. Laboratory abnormalities were graded according to the modified DAIDS version 1.0, with toxicity grades ranging from Grade 1 (mild) to Grade 4 (potentially life-threatening) . In the hepatic impairment study, one subject with severe hepatic impairment experienced two non-drug-related serious adverse events: an esophageal bleed requiring hospitalization and encephalopathy . No significant cardiotoxicity signals were observed, as GSK2336805 did not cause clinically meaningful QTc interval prolongation . For laboratory research, standard safety precautions (gloves, protective clothing, eye protection) should be followed when handling the compound. |
| References | |
| Additional Infomation |
41H (GSK2336805) is a novel, potent HCV NS5A inhibitor that emerged from a medicinal chemistry program exploring spiroketal pyrrolidine motifs. It was progressed to clinical trials based on its favorable potency, resistance profile, pharmacokinetics, and safety data [1].
The compound's putative binding mode involves spanning the NS5A dimer interface, with the 4-spiroketal pyrrolidine motif helping to stabilize interactions within the binding cavity, contributing to its high potency against wild-type and mutant viruses [1]. In clinical studies, 41H demonstrated good pharmacokinetics in single and multiple ascending dose studies in healthy volunteers and was well tolerated at doses up to 60 mg (single dose) and 75 mg (14-day multiple dose). In genotype 1 HCV-infected patients, a single dose of up to 120 mg resulted in a mean HCV RNA reduction of up to 2.95 log₁₀ copies/mL [1]. |
| Molecular Formula |
C42H52N8O8
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|---|---|
| Molecular Weight |
796.911089897156
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| Exact Mass |
796.39
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| Elemental Analysis |
C, 63.30; H, 6.58; N, 14.06; O, 16.06
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| CAS # |
1256390-53-0
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| PubChem CID |
57339460
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
1115.3±65.0 °C at 760 mmHg
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| Flash Point |
628.3±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.644
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| LogP |
5.44
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| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
13
|
| Heavy Atom Count |
58
|
| Complexity |
1430
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| Defined Atom Stereocenter Count |
4
|
| SMILES |
O1CCOC21CN(C([C@H](C(C)C)NC(=O)OC)=O)[C@H](C1=NC=C(C3C=CC(C4C=CC(=CC=4)C4=CN=C([C@@H]5CCCN5C([C@H](C(C)C)NC(=O)OC)=O)N4)=CC=3)N1)C2
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| InChi Key |
YMCAVGXTSCNFDE-BBACVFHCSA-N
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| InChi Code |
InChI=1S/C42H52N8O8/c1-24(2)34(47-40(53)55-5)38(51)49-17-7-8-32(49)36-43-21-30(45-36)28-13-9-26(10-14-28)27-11-15-29(16-12-27)31-22-44-37(46-31)33-20-42(57-18-19-58-42)23-50(33)39(52)35(25(3)4)48-41(54)56-6/h9-16,21-22,24-25,32-35H,7-8,17-20,23H2,1-6H3,(H,43,45)(H,44,46)(H,47,53)(H,48,54)/t32-,33-,34-,35-/m0/s1
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| Chemical Name |
methyl ((S)-1-((S)-8-(4-(4'-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-yl)carbamate
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| Synonyms |
GSK-2336805; GSK-805; JNJ-56914845; GSK 2336805; GSK2336805; GSK805; JNJ56914845; 0JD3P48M9V; GSK-805;
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2548 mL | 6.2742 mL | 12.5485 mL | |
| 5 mM | 0.2510 mL | 1.2548 mL | 2.5097 mL | |
| 10 mM | 0.1255 mL | 0.6274 mL | 1.2548 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.
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