- 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,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.
-
p. 971 - 983
(2007/10/03)
-
- Nonproteinogenic Amino Acids, II. - Synthesis and Determination of the Absolute Configuration of (2S,4S)-(-)- and (2S,4R)-(+)-5,5,5-Trifluoroleucine
-
The synthesis (Scheme 1) of racemic 4,4,4-trifluoro-3-methyl-1-butanol (5) and the resolution of its enantiomers is described.The absolute configuration of the negatively rotating enantiomer of 5 is correlated to that of the optically active fermentation amyl alcohol (S-10) via (S)-(-)-1,1,1-trifluoro-2-methylbutane (S-8) (Scheme 2).Oxidation of optically pure (R)-(+)-4,4,4-trifluoro-3-methyl-1-butanol (R-5) yields the aldehyde R-6 which is employed as starting material for the asymmetric Strecker synthesis of (2S,4R)-(+)-5,5,5-trifluoroleucine (13a).The analogous synthesis with (+/-)-4,4,4-trifluoro-3-methyl-1-butanol (6) via the aminonitrile 11 affords the optically pure (2S,4S)-diastereoisomer 11b which leads to enantiomerically pure (2S,4S)-(-)-5,5,5-trifluoroleucine (13b).
- Weinges, Klaus,Kromm, Erich
-
-
- ASYMMETRICAL REDUCTION OF PERFLUOROALKYLATED KETONES, KETOESTERS AND VINYL COMPOUNDS WITH BAKER'S YEAST
-
Reduction of perfluoroalkylated ketones, ketoesters and vinyl compounds with baker's yeast was studied.The ketones and β-ketoesters were asymmetrically reduced to give optically active perfluoroalkylated carbinols and hydroxyesters, while the vinyl compounds were reduced to perfluoroalkylated alkanes.
- Kitazume, Tomoya,Ishikawa, Nobuo
-
p. 237 - 238
(2007/10/02)
-