3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
Tedesco
Rosanna
R
Department of Medicinal Chemistry and Drug Metabolism, the Musculoskeletal, Microbial and Proliferative Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, USA. Rosanna_2_Tedesco@gsk.com
Shaw
Antony N
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Bambal
Ramesh
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Chai
Deping
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Concha
Nestor O
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Darcy
Michael G
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Dhanak
Dashyant
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Fitch
Duke M
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Gates
Adam
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Gerhardt
Warren G
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Halegoua
Dina L
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Han
Chao
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Hofmann
Glenn A
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Johnston
Victor K
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Kaura
Arun C
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Liu
Nannan
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Keenan
Richard M
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Lin-Goerke
Juili
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Sarisky
Robert T
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Wiggall
Kenneth J
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Zimmerman
Michael N
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Duffy
Kevin J
KJ
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D005838:Genotype; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D008252:Macaca fascicularis; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C508992:1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone; D000998:Antiviral Agents; D001581:Benzothiadiazines; D001798:Blood Proteins; D015363:Quinolones; D013829:Thiadiazines; D012324:RNA-Dependent RNA Polymerase