Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants.
Identifieur interne : 001042 ( Main/Exploration ); précédent : 001041; suivant : 001043Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants.
Auteurs : Wensheng Yu [États-Unis] ; Ling Tong [États-Unis] ; Bin Hu [République populaire de Chine] ; Bin Zhong [République populaire de Chine] ; Jinglai Hao [République populaire de Chine] ; Tao Ji [République populaire de Chine] ; Shuai Zan [République populaire de Chine] ; Craig A. Coburn [États-Unis] ; Oleg Selyutin [États-Unis] ; Lei Chen [États-Unis] ; Laura Rokosz [États-Unis] ; Sony Agrawal [États-Unis] ; Rong Liu [États-Unis] ; Stephanie Curry [États-Unis] ; Patricia Mcmonagle [États-Unis] ; Paul Ingravallo [États-Unis] ; Ernest Asante-Appiah [États-Unis] ; Shiying Chen [États-Unis] ; Joseph A. Kozlowski [États-Unis]Source :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Chiens, Chromanes (), Chromanes (pharmacologie), Chromanes (synthèse chimique), Découverte de médicament, Hepacivirus (), Mâle, Protéines virales non structurales (antagonistes et inhibiteurs), Rat Wistar, Rats, Relation dose-effet des médicaments, Relation structure-activité, Résistance virale aux médicaments (), Structure moléculaire, Tests de sensibilité microbienne.
- MESH :
- antagonistes et inhibiteurs : Protéines virales non structurales.
- pharmacologie : Antiviraux, Chromanes.
- synthèse chimique : Antiviraux, Chromanes.
- Animaux, Antiviraux, Chiens, Chromanes, Découverte de médicament, Hepacivirus, Mâle, Rat Wistar, Rats, Relation dose-effet des médicaments, Relation structure-activité, Résistance virale aux médicaments, Structure moléculaire, Tests de sensibilité microbienne.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Chromans (chemical synthesis), Chromans (chemistry), Chromans (pharmacology), Dogs, Dose-Response Relationship, Drug, Drug Discovery, Drug Resistance, Viral (drug effects), Hepacivirus (drug effects), Male, Microbial Sensitivity Tests, Molecular Structure, Rats, Rats, Wistar, Structure-Activity Relationship, Viral Nonstructural Proteins (antagonists & inhibitors).
- MESH :
- chemical , antagonists & inhibitors : Viral Nonstructural Proteins.
- chemical , chemical synthesis : Antiviral Agents, Chromans.
- chemical , chemistry : Antiviral Agents, Chromans.
- chemical , pharmacology : Antiviral Agents, Chromans.
- drug effects : Drug Resistance, Viral, Hepacivirus.
- Animals, Dogs, Dose-Response Relationship, Drug, Drug Discovery, Male, Microbial Sensitivity Tests, Molecular Structure, Rats, Rats, Wistar, Structure-Activity Relationship.
Abstract
The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors, such as compounds 14 and 25-28, with significantly improved potency against resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compound 14 also showed reasonable PK exposures in preclinical species (rat and dog).
DOI: 10.1021/acs.jmedchem.6b01234
PubMed: 27792320
Affiliations:
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Le document en format XML
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Coburn</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486</wicri:regionArea><wicri:noRegion>Pennsylvania 19486</wicri:noRegion></affiliation></author><author><name sortKey="Selyutin, Oleg" sort="Selyutin, Oleg" uniqKey="Selyutin O" first="Oleg" last="Selyutin">Oleg Selyutin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Lei" sort="Chen, Lei" uniqKey="Chen L" first="Lei" last="Chen">Lei Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></author><author><name sortKey="Rokosz, Laura" sort="Rokosz, Laura" uniqKey="Rokosz L" first="Laura" last="Rokosz">Laura Rokosz</name><affiliation wicri:level="1"><nlm:affiliation>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Agrawal, Sony" sort="Agrawal, Sony" uniqKey="Agrawal S" first="Sony" last="Agrawal">Sony Agrawal</name><affiliation wicri:level="1"><nlm:affiliation>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Rong" sort="Liu, Rong" uniqKey="Liu R" first="Rong" last="Liu">Rong Liu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Curry, Stephanie" sort="Curry, Stephanie" uniqKey="Curry S" first="Stephanie" last="Curry">Stephanie Curry</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Mcmonagle, Patricia" sort="Mcmonagle, Patricia" uniqKey="Mcmonagle P" first="Patricia" last="Mcmonagle">Patricia Mcmonagle</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Ingravallo, Paul" sort="Ingravallo, Paul" uniqKey="Ingravallo P" first="Paul" last="Ingravallo">Paul Ingravallo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Asante Appiah, Ernest" sort="Asante Appiah, Ernest" uniqKey="Asante Appiah E" first="Ernest" last="Asante-Appiah">Ernest Asante-Appiah</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Shiying" sort="Chen, Shiying" uniqKey="Chen S" first="Shiying" last="Chen">Shiying Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of PPDM, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of PPDM, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Kozlowski, Joseph A" sort="Kozlowski, Joseph A" uniqKey="Kozlowski J" first="Joseph A" last="Kozlowski">Joseph A. Kozlowski</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27792320</idno><idno type="pmid">27792320</idno><idno type="doi">10.1021/acs.jmedchem.6b01234</idno><idno type="wicri:Area/PubMed/Corpus">000B96</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000B96</idno><idno type="wicri:Area/PubMed/Curation">000B96</idno><idno type="wicri:explorRef" wicri:stream="PubMed" 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States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></author><author><name sortKey="Tong, Ling" sort="Tong, Ling" uniqKey="Tong L" first="Ling" last="Tong">Ling Tong</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></author><author><name sortKey="Hu, Bin" sort="Hu, Bin" uniqKey="Hu B" first="Bin" last="Hu">Bin Hu</name><affiliation wicri:level="1"><nlm:affiliation>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131</wicri:regionArea><wicri:noRegion>200131</wicri:noRegion></affiliation></author><author><name sortKey="Zhong, Bin" sort="Zhong, Bin" uniqKey="Zhong B" first="Bin" last="Zhong">Bin Zhong</name><affiliation wicri:level="1"><nlm:affiliation>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131</wicri:regionArea><wicri:noRegion>200131</wicri:noRegion></affiliation></author><author><name sortKey="Hao, Jinglai" sort="Hao, Jinglai" uniqKey="Hao J" first="Jinglai" last="Hao">Jinglai Hao</name><affiliation wicri:level="1"><nlm:affiliation>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131</wicri:regionArea><wicri:noRegion>200131</wicri:noRegion></affiliation></author><author><name sortKey="Ji, Tao" sort="Ji, Tao" uniqKey="Ji T" first="Tao" last="Ji">Tao Ji</name><affiliation wicri:level="1"><nlm:affiliation>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131</wicri:regionArea><wicri:noRegion>200131</wicri:noRegion></affiliation></author><author><name sortKey="Zan, Shuai" sort="Zan, Shuai" uniqKey="Zan S" first="Shuai" last="Zan">Shuai Zan</name><affiliation wicri:level="1"><nlm:affiliation>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131</wicri:regionArea><wicri:noRegion>200131</wicri:noRegion></affiliation></author><author><name sortKey="Coburn, Craig A" sort="Coburn, Craig A" uniqKey="Coburn C" first="Craig A" last="Coburn">Craig A. Coburn</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486</wicri:regionArea><wicri:noRegion>Pennsylvania 19486</wicri:noRegion></affiliation></author><author><name sortKey="Selyutin, Oleg" sort="Selyutin, Oleg" uniqKey="Selyutin O" first="Oleg" last="Selyutin">Oleg Selyutin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Lei" sort="Chen, Lei" uniqKey="Chen L" first="Lei" last="Chen">Lei Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></author><author><name sortKey="Rokosz, Laura" sort="Rokosz, Laura" uniqKey="Rokosz L" first="Laura" last="Rokosz">Laura Rokosz</name><affiliation wicri:level="1"><nlm:affiliation>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Agrawal, Sony" sort="Agrawal, Sony" uniqKey="Agrawal S" first="Sony" last="Agrawal">Sony Agrawal</name><affiliation wicri:level="1"><nlm:affiliation>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Rong" sort="Liu, Rong" uniqKey="Liu R" first="Rong" last="Liu">Rong Liu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Curry, Stephanie" sort="Curry, Stephanie" uniqKey="Curry S" first="Stephanie" last="Curry">Stephanie Curry</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Mcmonagle, Patricia" sort="Mcmonagle, Patricia" uniqKey="Mcmonagle P" first="Patricia" last="Mcmonagle">Patricia Mcmonagle</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Ingravallo, Paul" sort="Ingravallo, Paul" uniqKey="Ingravallo P" first="Paul" last="Ingravallo">Paul Ingravallo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Asante Appiah, Ernest" sort="Asante Appiah, Ernest" uniqKey="Asante Appiah E" first="Ernest" last="Asante-Appiah">Ernest Asante-Appiah</name><affiliation wicri:level="1"><nlm:affiliation>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Shiying" sort="Chen, Shiying" uniqKey="Chen S" first="Shiying" last="Chen">Shiying Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of PPDM, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of PPDM, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033</wicri:regionArea><wicri:noRegion>New Jersey 07033</wicri:noRegion></affiliation></author><author><name sortKey="Kozlowski, Joseph A" sort="Kozlowski, Joseph A" uniqKey="Kozlowski J" first="Joseph A" last="Kozlowski">Joseph A. Kozlowski</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065</wicri:regionArea><wicri:noRegion>Rahway New Jersey 07065</wicri:noRegion></affiliation></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></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Chromans (chemical synthesis)</term><term>Chromans (chemistry)</term><term>Chromans (pharmacology)</term><term>Dogs</term><term>Dose-Response Relationship, Drug</term><term>Drug Discovery</term><term>Drug Resistance, Viral (drug effects)</term><term>Hepacivirus (drug effects)</term><term>Male</term><term>Microbial Sensitivity Tests</term><term>Molecular Structure</term><term>Rats</term><term>Rats, Wistar</term><term>Structure-Activity Relationship</term><term>Viral Nonstructural Proteins (antagonists & inhibitors)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Antiviraux (synthèse chimique)</term><term>Chiens</term><term>Chromanes ()</term><term>Chromanes (pharmacologie)</term><term>Chromanes (synthèse chimique)</term><term>Découverte de médicament</term><term>Hepacivirus ()</term><term>Mâle</term><term>Protéines virales non structurales (antagonistes et inhibiteurs)</term><term>Rat Wistar</term><term>Rats</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Résistance virale aux médicaments ()</term><term>Structure moléculaire</term><term>Tests de sensibilité microbienne</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term><term>Chromans</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Chromans</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Chromans</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales non structurales</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Drug Resistance, Viral</term><term>Hepacivirus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Chromanes</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term><term>Chromanes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Dogs</term><term>Dose-Response Relationship, Drug</term><term>Drug Discovery</term><term>Male</term><term>Microbial Sensitivity Tests</term><term>Molecular Structure</term><term>Rats</term><term>Rats, Wistar</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Antiviraux</term><term>Chiens</term><term>Chromanes</term><term>Découverte de médicament</term><term>Hepacivirus</term><term>Mâle</term><term>Rat Wistar</term><term>Rats</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Résistance virale aux médicaments</term><term>Structure moléculaire</term><term>Tests de sensibilité microbienne</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors, such as compounds 14 and 25-28, with significantly improved potency against resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compound 14 also showed reasonable PK exposures in preclinical species (rat and dog).</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Yu, Wensheng" sort="Yu, Wensheng" uniqKey="Yu W" first="Wensheng" last="Yu">Wensheng Yu</name></noRegion><name sortKey="Agrawal, Sony" sort="Agrawal, Sony" uniqKey="Agrawal S" first="Sony" last="Agrawal">Sony Agrawal</name><name sortKey="Asante Appiah, Ernest" sort="Asante Appiah, Ernest" uniqKey="Asante Appiah E" first="Ernest" last="Asante-Appiah">Ernest Asante-Appiah</name><name sortKey="Chen, Lei" sort="Chen, Lei" uniqKey="Chen L" first="Lei" last="Chen">Lei Chen</name><name sortKey="Chen, Shiying" sort="Chen, Shiying" uniqKey="Chen S" first="Shiying" last="Chen">Shiying Chen</name><name sortKey="Coburn, Craig A" sort="Coburn, Craig A" uniqKey="Coburn C" first="Craig A" last="Coburn">Craig A. Coburn</name><name sortKey="Curry, Stephanie" sort="Curry, Stephanie" uniqKey="Curry S" first="Stephanie" last="Curry">Stephanie Curry</name><name sortKey="Ingravallo, Paul" sort="Ingravallo, Paul" uniqKey="Ingravallo P" first="Paul" last="Ingravallo">Paul Ingravallo</name><name sortKey="Kozlowski, Joseph A" sort="Kozlowski, Joseph A" uniqKey="Kozlowski J" first="Joseph A" last="Kozlowski">Joseph A. Kozlowski</name><name sortKey="Liu, Rong" sort="Liu, Rong" uniqKey="Liu R" first="Rong" last="Liu">Rong Liu</name><name sortKey="Mcmonagle, Patricia" sort="Mcmonagle, Patricia" uniqKey="Mcmonagle P" first="Patricia" last="Mcmonagle">Patricia Mcmonagle</name><name sortKey="Rokosz, Laura" sort="Rokosz, Laura" uniqKey="Rokosz L" first="Laura" last="Rokosz">Laura Rokosz</name><name sortKey="Selyutin, Oleg" sort="Selyutin, Oleg" uniqKey="Selyutin O" first="Oleg" last="Selyutin">Oleg Selyutin</name><name sortKey="Tong, Ling" sort="Tong, Ling" uniqKey="Tong L" first="Ling" last="Tong">Ling Tong</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Hu, Bin" sort="Hu, Bin" uniqKey="Hu B" first="Bin" last="Hu">Bin Hu</name></noRegion><name sortKey="Hao, Jinglai" sort="Hao, Jinglai" uniqKey="Hao J" first="Jinglai" last="Hao">Jinglai Hao</name><name sortKey="Ji, Tao" sort="Ji, Tao" uniqKey="Ji T" first="Tao" last="Ji">Tao Ji</name><name sortKey="Zan, Shuai" sort="Zan, Shuai" uniqKey="Zan S" first="Shuai" last="Zan">Shuai Zan</name><name sortKey="Zhong, Bin" sort="Zhong, Bin" uniqKey="Zhong B" first="Bin" last="Zhong">Bin Zhong</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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