Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-605339: A Novel HCV NS3 Protease Inhibitor

Jenkins, Susan; Scola, Paul M.; McPhee, Fiona; Knipe, Jay O.; Gesenberg, Christoph; Sinz, Michael; Arora, Vinod; Pilcher, Gary D.; Santone, Kenneth S.

doi:10.1002/jps.23959

Cited by 8 publications

(16 citation statements)

References 27 publications

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“…Therefore, the correlation between viral load decline (∼1 log drop) in clinical studies and efficacy in the viral replicon assay for a previous NS3 protease inhibitor, BMS‐605339, was used to set target plasma/liver C min levels for efficacy. The use of BMS‐605339 as a comparator for ASV was ideal since it had a similar potency in the GT 1a viral replicon assay (8 nM vs. 4 nM for ASV), similar binding to serum proteins (98%–99% vs. 97%–99% for ASV) and was hepatotropic like ASV (liver to plasma ratio in rat and dog was 55 vs. 40–359 for ASV) . Although this analysis predicts only efficacious plasma levels, it is the total concentration of ASV in the liver that was considered to have primary importance in determining antiviral activity) .…”

Section: Discussionmentioning

confidence: 99%

“…[33][34][35] Although this analysis predicts only efficacious plasma levels, it is the total concentration of ASV in the liver that was considered to have primary importance in determining antiviral activity). 33 A 1.2-1.8 log 10 viral load decline in HCV RNA was observed following a single 60-120 mg dose of BMS-605339 to patients infected with HCV GT 1. This equates to an estimated total liver level of between ß60 and 120 nM (ß 10 × 1a viral replicon EC 50 ).…”

Section: Discussionmentioning

confidence: 99%

“…The use of BMS‐605339 as a comparator for ASV was ideal since it had a similar potency in the GT 1a viral replicon assay (8 nM vs. 4 nM for ASV), similar binding to serum proteins (98%–99% vs. 97%–99% for ASV) and was hepatotropic like ASV (liver to plasma ratio in rat and dog was 55 vs. 40–359 for ASV) . Although this analysis predicts only efficacious plasma levels, it is the total concentration of ASV in the liver that was considered to have primary importance in determining antiviral activity) . A 1.2–1.8 log 10 viral load decline in HCV RNA was observed following a single 60–120 mg dose of BMS‐605339 to patients infected with HCV GT 1.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

Mosure

Knipe

Browning

et al. 2015

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

Mosure

Knipe

Browning

et al. 2015

Journal of Pharmaceutical Sciences

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“…ele: electrostatic contribution; vdw: van der Waals contribution; PB: polar contribution of desolvation; SA: nonpolar contribution of desolvation; bind: binding free energy; FC: fold change from and , which was calculated from the experimental EC 50. …”

Section: Resultsmentioning

confidence: 99%

“…The study of the nonclinical pharmacokinetic and metabolic properties of BMS by Jenkins et al. showed that BMS specifically targets HCV NS3 proteolytic activity of genotypes 1a and 1b, with EC 50 s of 8 and 3 nmol/L, respectively . Although BMS was a promising inhibitor for NS3 protease, several significant resistance mutations (D168C/Y/V, R155K, and N77S) were also detected.…”

Section: Introductionmentioning

confidence: 99%

Computational study on the drug resistance mechanism of HCV NS3 protease to BMS‐605339

Wang¹,

Guo²,

Chen³

et al. 2016

Biotech and App Biochem

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NS3 protease plays a vital role in the replication of the hepatitis C virus (HCV). BMS-605339 is a novel linear tetra-peptide α-ketoamide inhibitor of NS3 protease and shows specificity for HCV NS3 protease genotype 1a and genotype 1b. Mutation at the key site 168 of the HCV NS3 protease can induce resistance to BMS-605339, which greatly affects the antiviral therapy efficacy to hepatitis C. In the present study, we employed molecular dynamics simulations, free energy calculations, and free energy decomposition to explore the drug resistance mechanism of BMS-605339 due to the three representative mutations D168C/Y/V. The free energy decomposition analysis indicates that the decrease in the binding affinity is mainly attributed to the decrease in both van der Waals and electrostatic interactions. After detailed analysis of our calculated results, we observed that the break of the salt bridge between residues 155 and 168 caused by the mutations D168C/Y/V is the original reason for the decrease in the binding ability between BMS-605339 and the mutant NS3 proteases. The obtained results will reveal the drug resistance mechanism between BMS-605339 and the mutant NS3 proteases, and provide valuable clue for designing novel and more potent drugs to HCV NS3 protease.

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Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds

Wieske

Atilaw

Poongavanam

et al. 2022

Chemistry A European J

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The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d 6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d 6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.

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Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-605339: A Novel HCV NS3 Protease Inhibitor

Cited by 8 publications

References 27 publications

Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

Computational study on the drug resistance mechanism of HCV NS3 protease to BMS‐605339

Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds

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