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 |
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| Authors: | Tedesco Rosanna Shaw Antony N Bambal Ramesh Chai Deping Concha Nestor O Darcy Michael G Dhanak Dashyant Fitch Duke M Gates Adam Gerhardt Warren G Halegoua Dina L Han Chao Hofmann Glenn A Johnston Victor K Kaura Arun C Liu Nannan Keenan Richard M Lin-Goerke Juili Sarisky Robert T Wiggall Kenneth J Zimmerman Michael N Duffy Kevin J |
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| Affiliation: | 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 |
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| Abstract: | 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. |
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