SrasV1, Main, Exploration, bibRecord, 001041

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.

Identifieur interne : 001041 ( Main/Exploration ); précédent : 001040; suivant : 001042

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.

Auteurs : Li-Qiang Sun ; Eric Mull ; Barbara Zheng ; Stanley D'Andrea ; Qian Zhao ; Alan Xiangdong Wang ; Ny Sin ; Brian L. Venables ; Sing-Yuen Sit ; Yan Chen ; Jie Chen ; Anthony Cocuzza ; Donna M. Bilder ; Arvind Mathur [États-Unis] ; Richard Rampulla [États-Unis] ; Bang-Chi Chen [États-Unis] ; Theerthagiri Palani [Inde] ; Sivakumar Ganesan [Inde] ; Pirama Nayagam Arunachalam [Inde] ; Paul Falk ; Steven Levine ; Chaoqun Chen ; Jacques Friborg ; Fei Yu ; Dennis Hernandez ; Amy K. Sheaffer ; Jay O. Knipe ; Yong-Hae Han ; Richard Schartman ; Maria Donoso ; Kathy Mosure ; Michael W. Sinz ; Tatyana Zvyaga ; Ramkumar Rajamani ; Kevin Kish ; Jeffrey Tredup ; Herbert E. Klei ; Qi Gao [États-Unis] ; Alicia Ng [États-Unis] ; Luciano Mueller ; Dennis M. Grasela ; Stephen Adams [États-Unis] ; James Loy ; Paul C. Levesque [États-Unis] ; Huabin Sun [États-Unis] ; Hong Shi [États-Unis] ; Lucy Sun [États-Unis] ; William Warner [États-Unis] ; Danshi Li [États-Unis] ; Jialong Zhu [États-Unis] ; Ying-Kai Wang ; Hua Fang ; Mark I. Cockett ; Nicholas A. Meanwell ; Fiona Mcphee ; Paul M. Scola

Source :

Journal of medicinal chemistry [ 1520-4804 ] ; 2016.

RBID : pubmed:27564532

Descripteurs français

KwdFr :
- Animaux, Antiviraux (), Antiviraux (administration et posologie), Antiviraux (pharmacocinétique), Antiviraux (pharmacologie), Calendrier d'administration des médicaments, Chiens, Hepacivirus (), Hepacivirus (génétique), Isoquinoléines (usage thérapeutique), Lapins, Macaca fascicularis, Modèles moléculaires, Mâle, Oligopeptides (), Oligopeptides (administration et posologie), Oligopeptides (pharmacocinétique), Oligopeptides (pharmacologie), Protéines virales non structurales (antagonistes et inhibiteurs), Rat Sprague-Dawley, Relation structure-activité, Réplicon, Résistance virale aux médicaments, Stéréoisomérie, Sulfonamides (), Sulfonamides (administration et posologie), Sulfonamides (pharmacocinétique), Sulfonamides (pharmacologie), Sulfonamides (usage thérapeutique).
MESH :
- administration et posologie : Antiviraux, Oligopeptides, Sulfonamides.
- antagonistes et inhibiteurs : Protéines virales non structurales.
- génétique : Hepacivirus.
- pharmacocinétique : Antiviraux, Oligopeptides, Sulfonamides.
- pharmacologie : Antiviraux, Oligopeptides, Sulfonamides.
- usage thérapeutique : Isoquinoléines, Sulfonamides.
- Animaux, Antiviraux, Calendrier d'administration des médicaments, Chiens, Hepacivirus, Lapins, Macaca fascicularis, Modèles moléculaires, Mâle, Oligopeptides, Rat Sprague-Dawley, Relation structure-activité, Réplicon, Résistance virale aux médicaments, Stéréoisomérie, Sulfonamides.

English descriptors

KwdEn :
- Animals, Antiviral Agents (administration & dosage), Antiviral Agents (chemistry), Antiviral Agents (pharmacokinetics), Antiviral Agents (pharmacology), Dogs, Drug Administration Schedule, Drug Resistance, Viral, Hepacivirus (drug effects), Hepacivirus (genetics), Isoquinolines (therapeutic use), Macaca fascicularis, Male, Models, Molecular, Oligopeptides (administration & dosage), Oligopeptides (chemistry), Oligopeptides (pharmacokinetics), Oligopeptides (pharmacology), Rabbits, Rats, Sprague-Dawley, Replicon, Stereoisomerism, Structure-Activity Relationship, Sulfonamides (administration & dosage), Sulfonamides (chemistry), Sulfonamides (pharmacokinetics), Sulfonamides (pharmacology), Sulfonamides (therapeutic use), Viral Nonstructural Proteins (antagonists & inhibitors).
MESH :
- chemical , administration & dosage : Antiviral Agents, Oligopeptides, Sulfonamides.
- chemical , antagonists & inhibitors : Viral Nonstructural Proteins.
- chemical , chemistry : Antiviral Agents, Oligopeptides, Sulfonamides.
- chemical , pharmacokinetics : Antiviral Agents, Oligopeptides, Sulfonamides.
- chemical , pharmacology : Antiviral Agents, Oligopeptides, Sulfonamides.
- drug effects : Hepacivirus.
- genetics : Hepacivirus.
- chemical , therapeutic use : Isoquinolines, Sulfonamides.
- Animals, Dogs, Drug Administration Schedule, Drug Resistance, Viral, Macaca fascicularis, Male, Models, Molecular, Rabbits, Rats, Sprague-Dawley, Replicon, Stereoisomerism, Structure-Activity Relationship.

Abstract

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).

DOI: 10.1021/acs.jmedchem.6b00821
PubMed: 27564532

Affiliations:

Inde, États-Unis

Le document en format XML

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<author><name sortKey="Adams, Stephen" sort="Adams, Stephen" uniqKey="Adams S" first="Stephen" last="Adams">Stephen Adams</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
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<author><name sortKey="Sun, Huabin" sort="Sun, Huabin" uniqKey="Sun H" first="Huabin" last="Sun">Huabin Sun</name>
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<country xml:lang="fr">États-Unis</country>
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<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Shi, Hong" sort="Shi, Hong" uniqKey="Shi H" first="Hong" last="Shi">Hong Shi</name>
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<country xml:lang="fr">États-Unis</country>
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</author>
<author><name sortKey="Sun, Lucy" sort="Sun, Lucy" uniqKey="Sun L" first="Lucy" last="Sun">Lucy Sun</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Warner, William" sort="Warner, William" uniqKey="Warner W" first="William" last="Warner">William Warner</name>
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<country xml:lang="fr">États-Unis</country>
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</affiliation>
</author>
<author><name sortKey="Li, Danshi" sort="Li, Danshi" uniqKey="Li D" first="Danshi" last="Li">Danshi Li</name>
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<country xml:lang="fr">États-Unis</country>
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<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zhu, Jialong" sort="Zhu, Jialong" uniqKey="Zhu J" first="Jialong" last="Zhu">Jialong Zhu</name>
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<country xml:lang="fr">États-Unis</country>
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<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wang, Ying Kai" sort="Wang, Ying Kai" uniqKey="Wang Y" first="Ying-Kai" last="Wang">Ying-Kai Wang</name>
</author>
<author><name sortKey="Fang, Hua" sort="Fang, Hua" uniqKey="Fang H" first="Hua" last="Fang">Hua Fang</name>
</author>
<author><name sortKey="Cockett, Mark I" sort="Cockett, Mark I" uniqKey="Cockett M" first="Mark I" last="Cockett">Mark I. Cockett</name>
</author>
<author><name sortKey="Meanwell, Nicholas A" sort="Meanwell, Nicholas A" uniqKey="Meanwell N" first="Nicholas A" last="Meanwell">Nicholas A. Meanwell</name>
</author>
<author><name sortKey="Mcphee, Fiona" sort="Mcphee, Fiona" uniqKey="Mcphee F" first="Fiona" last="Mcphee">Fiona Mcphee</name>
</author>
<author><name sortKey="Scola, Paul M" sort="Scola, Paul M" uniqKey="Scola P" first="Paul M" last="Scola">Paul M. Scola</name>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.</title>
<author><name sortKey="Sun, Li Qiang" sort="Sun, Li Qiang" uniqKey="Sun L" first="Li-Qiang" last="Sun">Li-Qiang Sun</name>
</author>
<author><name sortKey="Mull, Eric" sort="Mull, Eric" uniqKey="Mull E" first="Eric" last="Mull">Eric Mull</name>
</author>
<author><name sortKey="Zheng, Barbara" sort="Zheng, Barbara" uniqKey="Zheng B" first="Barbara" last="Zheng">Barbara Zheng</name>
</author>
<author><name sortKey="D Andrea, Stanley" sort="D Andrea, Stanley" uniqKey="D Andrea S" first="Stanley" last="D'Andrea">Stanley D'Andrea</name>
</author>
<author><name sortKey="Zhao, Qian" sort="Zhao, Qian" uniqKey="Zhao Q" first="Qian" last="Zhao">Qian Zhao</name>
</author>
<author><name sortKey="Wang, Alan Xiangdong" sort="Wang, Alan Xiangdong" uniqKey="Wang A" first="Alan Xiangdong" last="Wang">Alan Xiangdong Wang</name>
</author>
<author><name sortKey="Sin, Ny" sort="Sin, Ny" uniqKey="Sin N" first="Ny" last="Sin">Ny Sin</name>
</author>
<author><name sortKey="Venables, Brian L" sort="Venables, Brian L" uniqKey="Venables B" first="Brian L" last="Venables">Brian L. Venables</name>
</author>
<author><name sortKey="Sit, Sing Yuen" sort="Sit, Sing Yuen" uniqKey="Sit S" first="Sing-Yuen" last="Sit">Sing-Yuen Sit</name>
</author>
<author><name sortKey="Chen, Yan" sort="Chen, Yan" uniqKey="Chen Y" first="Yan" last="Chen">Yan Chen</name>
</author>
<author><name sortKey="Chen, Jie" sort="Chen, Jie" uniqKey="Chen J" first="Jie" last="Chen">Jie Chen</name>
</author>
<author><name sortKey="Cocuzza, Anthony" sort="Cocuzza, Anthony" uniqKey="Cocuzza A" first="Anthony" last="Cocuzza">Anthony Cocuzza</name>
</author>
<author><name sortKey="Bilder, Donna M" sort="Bilder, Donna M" uniqKey="Bilder D" first="Donna M" last="Bilder">Donna M. Bilder</name>
</author>
<author><name sortKey="Mathur, Arvind" sort="Mathur, Arvind" uniqKey="Mathur A" first="Arvind" last="Mathur">Arvind Mathur</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543</wicri:regionArea>
<wicri:noRegion>New Jersey 08543</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Rampulla, Richard" sort="Rampulla, Richard" uniqKey="Rampulla R" first="Richard" last="Rampulla">Richard Rampulla</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543</wicri:regionArea>
<wicri:noRegion>New Jersey 08543</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chen, Bang Chi" sort="Chen, Bang Chi" uniqKey="Chen B" first="Bang-Chi" last="Chen">Bang-Chi Chen</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543</wicri:regionArea>
<wicri:noRegion>New Jersey 08543</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Palani, Theerthagiri" sort="Palani, Theerthagiri" uniqKey="Palani T" first="Theerthagiri" last="Palani">Theerthagiri Palani</name>
<affiliation wicri:level="1"><nlm:affiliation>Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099</wicri:regionArea>
<wicri:noRegion>Bangalore 560099</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ganesan, Sivakumar" sort="Ganesan, Sivakumar" uniqKey="Ganesan S" first="Sivakumar" last="Ganesan">Sivakumar Ganesan</name>
<affiliation wicri:level="1"><nlm:affiliation>Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099</wicri:regionArea>
<wicri:noRegion>Bangalore 560099</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Arunachalam, Pirama Nayagam" sort="Arunachalam, Pirama Nayagam" uniqKey="Arunachalam P" first="Pirama Nayagam" last="Arunachalam">Pirama Nayagam Arunachalam</name>
<affiliation wicri:level="1"><nlm:affiliation>Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099</wicri:regionArea>
<wicri:noRegion>Bangalore 560099</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Falk, Paul" sort="Falk, Paul" uniqKey="Falk P" first="Paul" last="Falk">Paul Falk</name>
</author>
<author><name sortKey="Levine, Steven" sort="Levine, Steven" uniqKey="Levine S" first="Steven" last="Levine">Steven Levine</name>
</author>
<author><name sortKey="Chen, Chaoqun" sort="Chen, Chaoqun" uniqKey="Chen C" first="Chaoqun" last="Chen">Chaoqun Chen</name>
</author>
<author><name sortKey="Friborg, Jacques" sort="Friborg, Jacques" uniqKey="Friborg J" first="Jacques" last="Friborg">Jacques Friborg</name>
</author>
<author><name sortKey="Yu, Fei" sort="Yu, Fei" uniqKey="Yu F" first="Fei" last="Yu">Fei Yu</name>
</author>
<author><name sortKey="Hernandez, Dennis" sort="Hernandez, Dennis" uniqKey="Hernandez D" first="Dennis" last="Hernandez">Dennis Hernandez</name>
</author>
<author><name sortKey="Sheaffer, Amy K" sort="Sheaffer, Amy K" uniqKey="Sheaffer A" first="Amy K" last="Sheaffer">Amy K. Sheaffer</name>
</author>
<author><name sortKey="Knipe, Jay O" sort="Knipe, Jay O" uniqKey="Knipe J" first="Jay O" last="Knipe">Jay O. Knipe</name>
</author>
<author><name sortKey="Han, Yong Hae" sort="Han, Yong Hae" uniqKey="Han Y" first="Yong-Hae" last="Han">Yong-Hae Han</name>
</author>
<author><name sortKey="Schartman, Richard" sort="Schartman, Richard" uniqKey="Schartman R" first="Richard" last="Schartman">Richard Schartman</name>
</author>
<author><name sortKey="Donoso, Maria" sort="Donoso, Maria" uniqKey="Donoso M" first="Maria" last="Donoso">Maria Donoso</name>
</author>
<author><name sortKey="Mosure, Kathy" sort="Mosure, Kathy" uniqKey="Mosure K" first="Kathy" last="Mosure">Kathy Mosure</name>
</author>
<author><name sortKey="Sinz, Michael W" sort="Sinz, Michael W" uniqKey="Sinz M" first="Michael W" last="Sinz">Michael W. Sinz</name>
</author>
<author><name sortKey="Zvyaga, Tatyana" sort="Zvyaga, Tatyana" uniqKey="Zvyaga T" first="Tatyana" last="Zvyaga">Tatyana Zvyaga</name>
</author>
<author><name sortKey="Rajamani, Ramkumar" sort="Rajamani, Ramkumar" uniqKey="Rajamani R" first="Ramkumar" last="Rajamani">Ramkumar Rajamani</name>
</author>
<author><name sortKey="Kish, Kevin" sort="Kish, Kevin" uniqKey="Kish K" first="Kevin" last="Kish">Kevin Kish</name>
</author>
<author><name sortKey="Tredup, Jeffrey" sort="Tredup, Jeffrey" uniqKey="Tredup J" first="Jeffrey" last="Tredup">Jeffrey Tredup</name>
</author>
<author><name sortKey="Klei, Herbert E" sort="Klei, Herbert E" uniqKey="Klei H" first="Herbert E" last="Klei">Herbert E. Klei</name>
</author>
<author><name sortKey="Gao, Qi" sort="Gao, Qi" uniqKey="Gao Q" first="Qi" last="Gao">Qi Gao</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903</wicri:regionArea>
<wicri:noRegion>New Jersey 08903</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ng, Alicia" sort="Ng, Alicia" uniqKey="Ng A" first="Alicia" last="Ng">Alicia Ng</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903</wicri:regionArea>
<wicri:noRegion>New Jersey 08903</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mueller, Luciano" sort="Mueller, Luciano" uniqKey="Mueller L" first="Luciano" last="Mueller">Luciano Mueller</name>
</author>
<author><name sortKey="Grasela, Dennis M" sort="Grasela, Dennis M" uniqKey="Grasela D" first="Dennis M" last="Grasela">Dennis M. Grasela</name>
</author>
<author><name sortKey="Adams, Stephen" sort="Adams, Stephen" uniqKey="Adams S" first="Stephen" last="Adams">Stephen Adams</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Loy, James" sort="Loy, James" uniqKey="Loy J" first="James" last="Loy">James Loy</name>
</author>
<author><name sortKey="Levesque, Paul C" sort="Levesque, Paul C" uniqKey="Levesque P" first="Paul C" last="Levesque">Paul C. Levesque</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Sun, Huabin" sort="Sun, Huabin" uniqKey="Sun H" first="Huabin" last="Sun">Huabin Sun</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Shi, Hong" sort="Shi, Hong" uniqKey="Shi H" first="Hong" last="Shi">Hong Shi</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Sun, Lucy" sort="Sun, Lucy" uniqKey="Sun L" first="Lucy" last="Sun">Lucy Sun</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Warner, William" sort="Warner, William" uniqKey="Warner W" first="William" last="Warner">William Warner</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Li, Danshi" sort="Li, Danshi" uniqKey="Li D" first="Danshi" last="Li">Danshi Li</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zhu, Jialong" sort="Zhu, Jialong" uniqKey="Zhu J" first="Jialong" last="Zhu">Jialong Zhu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534</wicri:regionArea>
<wicri:noRegion>New Jersey 08534</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wang, Ying Kai" sort="Wang, Ying Kai" uniqKey="Wang Y" first="Ying-Kai" last="Wang">Ying-Kai Wang</name>
</author>
<author><name sortKey="Fang, Hua" sort="Fang, Hua" uniqKey="Fang H" first="Hua" last="Fang">Hua Fang</name>
</author>
<author><name sortKey="Cockett, Mark I" sort="Cockett, Mark I" uniqKey="Cockett M" first="Mark I" last="Cockett">Mark I. Cockett</name>
</author>
<author><name sortKey="Meanwell, Nicholas A" sort="Meanwell, Nicholas A" uniqKey="Meanwell N" first="Nicholas A" last="Meanwell">Nicholas A. Meanwell</name>
</author>
<author><name sortKey="Mcphee, Fiona" sort="Mcphee, Fiona" uniqKey="Mcphee F" first="Fiona" last="Mcphee">Fiona Mcphee</name>
</author>
<author><name sortKey="Scola, Paul M" sort="Scola, Paul M" uniqKey="Scola P" first="Paul M" last="Scola">Paul M. Scola</name>
</author>
</analytic>
<series><title level="j">Journal of medicinal chemistry</title>
<idno type="eISSN">1520-4804</idno>
<imprint><date when="2016" type="published">2016</date>
</imprint>
</series>
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<term>Antiviral Agents (administration & dosage)</term>
<term>Antiviral Agents (chemistry)</term>
<term>Antiviral Agents (pharmacokinetics)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Dogs</term>
<term>Drug Administration Schedule</term>
<term>Drug Resistance, Viral</term>
<term>Hepacivirus (drug effects)</term>
<term>Hepacivirus (genetics)</term>
<term>Isoquinolines (therapeutic use)</term>
<term>Macaca fascicularis</term>
<term>Male</term>
<term>Models, Molecular</term>
<term>Oligopeptides (administration & dosage)</term>
<term>Oligopeptides (chemistry)</term>
<term>Oligopeptides (pharmacokinetics)</term>
<term>Oligopeptides (pharmacology)</term>
<term>Rabbits</term>
<term>Rats, Sprague-Dawley</term>
<term>Replicon</term>
<term>Stereoisomerism</term>
<term>Structure-Activity Relationship</term>
<term>Sulfonamides (administration & dosage)</term>
<term>Sulfonamides (chemistry)</term>
<term>Sulfonamides (pharmacokinetics)</term>
<term>Sulfonamides (pharmacology)</term>
<term>Sulfonamides (therapeutic use)</term>
<term>Viral Nonstructural Proteins (antagonists & inhibitors)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antiviraux ()</term>
<term>Antiviraux (administration et posologie)</term>
<term>Antiviraux (pharmacocinétique)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Calendrier d'administration des médicaments</term>
<term>Chiens</term>
<term>Hepacivirus ()</term>
<term>Hepacivirus (génétique)</term>
<term>Isoquinoléines (usage thérapeutique)</term>
<term>Lapins</term>
<term>Macaca fascicularis</term>
<term>Modèles moléculaires</term>
<term>Mâle</term>
<term>Oligopeptides ()</term>
<term>Oligopeptides (administration et posologie)</term>
<term>Oligopeptides (pharmacocinétique)</term>
<term>Oligopeptides (pharmacologie)</term>
<term>Protéines virales non structurales (antagonistes et inhibiteurs)</term>
<term>Rat Sprague-Dawley</term>
<term>Relation structure-activité</term>
<term>Réplicon</term>
<term>Résistance virale aux médicaments</term>
<term>Stéréoisomérie</term>
<term>Sulfonamides ()</term>
<term>Sulfonamides (administration et posologie)</term>
<term>Sulfonamides (pharmacocinétique)</term>
<term>Sulfonamides (pharmacologie)</term>
<term>Sulfonamides (usage thérapeutique)</term>
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<term>Oligopeptides</term>
<term>Sulfonamides</term>
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</keywords>
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<term>Oligopeptides</term>
<term>Sulfonamides</term>
</keywords>
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<term>Oligopeptides</term>
<term>Sulfonamides</term>
</keywords>
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<term>Oligopeptides</term>
<term>Sulfonamides</term>
</keywords>
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<term>Oligopeptides</term>
<term>Sulfonamides</term>
</keywords>
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</keywords>
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</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Hepacivirus</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Hepacivirus</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Antiviraux</term>
<term>Oligopeptides</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Oligopeptides</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Isoquinolines</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Isoquinoléines</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Dogs</term>
<term>Drug Administration Schedule</term>
<term>Drug Resistance, Viral</term>
<term>Macaca fascicularis</term>
<term>Male</term>
<term>Models, Molecular</term>
<term>Rabbits</term>
<term>Rats, Sprague-Dawley</term>
<term>Replicon</term>
<term>Stereoisomerism</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Antiviraux</term>
<term>Calendrier d'administration des médicaments</term>
<term>Chiens</term>
<term>Hepacivirus</term>
<term>Lapins</term>
<term>Macaca fascicularis</term>
<term>Modèles moléculaires</term>
<term>Mâle</term>
<term>Oligopeptides</term>
<term>Rat Sprague-Dawley</term>
<term>Relation structure-activité</term>
<term>Réplicon</term>
<term>Résistance virale aux médicaments</term>
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<front><div type="abstract" xml:lang="en">The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).</div>
</front>
</TEI>
<affiliations><list><country><li>Inde</li>
<li>États-Unis</li>
</country>
</list>
<tree><noCountry><name sortKey="Bilder, Donna M" sort="Bilder, Donna M" uniqKey="Bilder D" first="Donna M" last="Bilder">Donna M. Bilder</name>
<name sortKey="Chen, Chaoqun" sort="Chen, Chaoqun" uniqKey="Chen C" first="Chaoqun" last="Chen">Chaoqun Chen</name>
<name sortKey="Chen, Jie" sort="Chen, Jie" uniqKey="Chen J" first="Jie" last="Chen">Jie Chen</name>
<name sortKey="Chen, Yan" sort="Chen, Yan" uniqKey="Chen Y" first="Yan" last="Chen">Yan Chen</name>
<name sortKey="Cockett, Mark I" sort="Cockett, Mark I" uniqKey="Cockett M" first="Mark I" last="Cockett">Mark I. Cockett</name>
<name sortKey="Cocuzza, Anthony" sort="Cocuzza, Anthony" uniqKey="Cocuzza A" first="Anthony" last="Cocuzza">Anthony Cocuzza</name>
<name sortKey="D Andrea, Stanley" sort="D Andrea, Stanley" uniqKey="D Andrea S" first="Stanley" last="D'Andrea">Stanley D'Andrea</name>
<name sortKey="Donoso, Maria" sort="Donoso, Maria" uniqKey="Donoso M" first="Maria" last="Donoso">Maria Donoso</name>
<name sortKey="Falk, Paul" sort="Falk, Paul" uniqKey="Falk P" first="Paul" last="Falk">Paul Falk</name>
<name sortKey="Fang, Hua" sort="Fang, Hua" uniqKey="Fang H" first="Hua" last="Fang">Hua Fang</name>
<name sortKey="Friborg, Jacques" sort="Friborg, Jacques" uniqKey="Friborg J" first="Jacques" last="Friborg">Jacques Friborg</name>
<name sortKey="Grasela, Dennis M" sort="Grasela, Dennis M" uniqKey="Grasela D" first="Dennis M" last="Grasela">Dennis M. Grasela</name>
<name sortKey="Han, Yong Hae" sort="Han, Yong Hae" uniqKey="Han Y" first="Yong-Hae" last="Han">Yong-Hae Han</name>
<name sortKey="Hernandez, Dennis" sort="Hernandez, Dennis" uniqKey="Hernandez D" first="Dennis" last="Hernandez">Dennis Hernandez</name>
<name sortKey="Kish, Kevin" sort="Kish, Kevin" uniqKey="Kish K" first="Kevin" last="Kish">Kevin Kish</name>
<name sortKey="Klei, Herbert E" sort="Klei, Herbert E" uniqKey="Klei H" first="Herbert E" last="Klei">Herbert E. Klei</name>
<name sortKey="Knipe, Jay O" sort="Knipe, Jay O" uniqKey="Knipe J" first="Jay O" last="Knipe">Jay O. Knipe</name>
<name sortKey="Levine, Steven" sort="Levine, Steven" uniqKey="Levine S" first="Steven" last="Levine">Steven Levine</name>
<name sortKey="Loy, James" sort="Loy, James" uniqKey="Loy J" first="James" last="Loy">James Loy</name>
<name sortKey="Mcphee, Fiona" sort="Mcphee, Fiona" uniqKey="Mcphee F" first="Fiona" last="Mcphee">Fiona Mcphee</name>
<name sortKey="Meanwell, Nicholas A" sort="Meanwell, Nicholas A" uniqKey="Meanwell N" first="Nicholas A" last="Meanwell">Nicholas A. Meanwell</name>
<name sortKey="Mosure, Kathy" sort="Mosure, Kathy" uniqKey="Mosure K" first="Kathy" last="Mosure">Kathy Mosure</name>
<name sortKey="Mueller, Luciano" sort="Mueller, Luciano" uniqKey="Mueller L" first="Luciano" last="Mueller">Luciano Mueller</name>
<name sortKey="Mull, Eric" sort="Mull, Eric" uniqKey="Mull E" first="Eric" last="Mull">Eric Mull</name>
<name sortKey="Rajamani, Ramkumar" sort="Rajamani, Ramkumar" uniqKey="Rajamani R" first="Ramkumar" last="Rajamani">Ramkumar Rajamani</name>
<name sortKey="Schartman, Richard" sort="Schartman, Richard" uniqKey="Schartman R" first="Richard" last="Schartman">Richard Schartman</name>
<name sortKey="Scola, Paul M" sort="Scola, Paul M" uniqKey="Scola P" first="Paul M" last="Scola">Paul M. Scola</name>
<name sortKey="Sheaffer, Amy K" sort="Sheaffer, Amy K" uniqKey="Sheaffer A" first="Amy K" last="Sheaffer">Amy K. Sheaffer</name>
<name sortKey="Sin, Ny" sort="Sin, Ny" uniqKey="Sin N" first="Ny" last="Sin">Ny Sin</name>
<name sortKey="Sinz, Michael W" sort="Sinz, Michael W" uniqKey="Sinz M" first="Michael W" last="Sinz">Michael W. Sinz</name>
<name sortKey="Sit, Sing Yuen" sort="Sit, Sing Yuen" uniqKey="Sit S" first="Sing-Yuen" last="Sit">Sing-Yuen Sit</name>
<name sortKey="Sun, Li Qiang" sort="Sun, Li Qiang" uniqKey="Sun L" first="Li-Qiang" last="Sun">Li-Qiang Sun</name>
<name sortKey="Tredup, Jeffrey" sort="Tredup, Jeffrey" uniqKey="Tredup J" first="Jeffrey" last="Tredup">Jeffrey Tredup</name>
<name sortKey="Venables, Brian L" sort="Venables, Brian L" uniqKey="Venables B" first="Brian L" last="Venables">Brian L. Venables</name>
<name sortKey="Wang, Alan Xiangdong" sort="Wang, Alan Xiangdong" uniqKey="Wang A" first="Alan Xiangdong" last="Wang">Alan Xiangdong Wang</name>
<name sortKey="Wang, Ying Kai" sort="Wang, Ying Kai" uniqKey="Wang Y" first="Ying-Kai" last="Wang">Ying-Kai Wang</name>
<name sortKey="Yu, Fei" sort="Yu, Fei" uniqKey="Yu F" first="Fei" last="Yu">Fei Yu</name>
<name sortKey="Zhao, Qian" sort="Zhao, Qian" uniqKey="Zhao Q" first="Qian" last="Zhao">Qian Zhao</name>
<name sortKey="Zheng, Barbara" sort="Zheng, Barbara" uniqKey="Zheng B" first="Barbara" last="Zheng">Barbara Zheng</name>
<name sortKey="Zvyaga, Tatyana" sort="Zvyaga, Tatyana" uniqKey="Zvyaga T" first="Tatyana" last="Zvyaga">Tatyana Zvyaga</name>
</noCountry>
<country name="États-Unis"><noRegion><name sortKey="Mathur, Arvind" sort="Mathur, Arvind" uniqKey="Mathur A" first="Arvind" last="Mathur">Arvind Mathur</name>
</noRegion>
<name sortKey="Adams, Stephen" sort="Adams, Stephen" uniqKey="Adams S" first="Stephen" last="Adams">Stephen Adams</name>
<name sortKey="Chen, Bang Chi" sort="Chen, Bang Chi" uniqKey="Chen B" first="Bang-Chi" last="Chen">Bang-Chi Chen</name>
<name sortKey="Gao, Qi" sort="Gao, Qi" uniqKey="Gao Q" first="Qi" last="Gao">Qi Gao</name>
<name sortKey="Levesque, Paul C" sort="Levesque, Paul C" uniqKey="Levesque P" first="Paul C" last="Levesque">Paul C. Levesque</name>
<name sortKey="Li, Danshi" sort="Li, Danshi" uniqKey="Li D" first="Danshi" last="Li">Danshi Li</name>
<name sortKey="Ng, Alicia" sort="Ng, Alicia" uniqKey="Ng A" first="Alicia" last="Ng">Alicia Ng</name>
<name sortKey="Rampulla, Richard" sort="Rampulla, Richard" uniqKey="Rampulla R" first="Richard" last="Rampulla">Richard Rampulla</name>
<name sortKey="Shi, Hong" sort="Shi, Hong" uniqKey="Shi H" first="Hong" last="Shi">Hong Shi</name>
<name sortKey="Sun, Huabin" sort="Sun, Huabin" uniqKey="Sun H" first="Huabin" last="Sun">Huabin Sun</name>
<name sortKey="Sun, Lucy" sort="Sun, Lucy" uniqKey="Sun L" first="Lucy" last="Sun">Lucy Sun</name>
<name sortKey="Warner, William" sort="Warner, William" uniqKey="Warner W" first="William" last="Warner">William Warner</name>
<name sortKey="Zhu, Jialong" sort="Zhu, Jialong" uniqKey="Zhu J" first="Jialong" last="Zhu">Jialong Zhu</name>
</country>
<country name="Inde"><noRegion><name sortKey="Palani, Theerthagiri" sort="Palani, Theerthagiri" uniqKey="Palani T" first="Theerthagiri" last="Palani">Theerthagiri Palani</name>
</noRegion>
<name sortKey="Arunachalam, Pirama Nayagam" sort="Arunachalam, Pirama Nayagam" uniqKey="Arunachalam P" first="Pirama Nayagam" last="Arunachalam">Pirama Nayagam Arunachalam</name>
<name sortKey="Ganesan, Sivakumar" sort="Ganesan, Sivakumar" uniqKey="Ganesan S" first="Sivakumar" last="Ganesan">Sivakumar Ganesan</name>
</country>
</tree>
</affiliations>
</record>

Pour manipuler ce document sous Unix (Dilib)

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HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001041 | SxmlIndent | more

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{{Explor lien
   |wiki=    Sante
   |area=    SrasV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     pubmed:27564532
   |texte=   Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.
}}

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       | NlmPubMed2Wicri -a SrasV1

This area was generated with Dilib version V0.6.33.
Data generation: Tue Apr 28 14:49:16 2020. Site generation: Sat Mar 27 22:06:49 2021

Serveur d'exploration SRAS

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.

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