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Start Over Author "Fell JB" Topic dna-directed rna polymerases
2 results on '"Fell JB"'

1. Non-nucleoside inhibitors of HCV NS5B polymerase. Part 1: Synthetic and computational exploration of the binding modes of benzothiadiazine and 1,4-benzothiazine HCV NS5b polymerase inhibitors.

Author

Hendricks RT, Fell JB, Blake JF, Fischer JP, Robinson JE, Spencer SR, Stengel PJ, Bernacki AL, Leveque VJ, Le Pogam S, Rajyaguru S, Najera I, Josey JA, Harris JR, and Swallow S

Subjects
Antiviral Agents chemistry, Antiviral Agents pharmacology, Benzothiadiazines chemistry, Benzothiadiazines pharmacology, Computational Biology, Computer Simulation, Crystallography, X-Ray, DNA-Directed RNA Polymerases metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Protein Binding, Structure-Activity Relationship, Thiazines chemistry, Thiazines pharmacology, Viral Nonstructural Proteins metabolism, Virus Replication drug effects, Antiviral Agents chemical synthesis, Benzothiadiazines chemical synthesis, DNA-Directed RNA Polymerases antagonists & inhibitors, Enzyme Inhibitors chemical synthesis, Hepacivirus drug effects, Thiazines chemical synthesis, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.

Published
2009
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2. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: Synthesis and structure-activity relationships of benzothiazine-substituted quinolinediones.

Author

de Vicente J, Hendricks RT, Smith DB, Fell JB, Fischer J, Spencer SR, Stengel PJ, Mohr P, Robinson JE, Blake JF, Hilgenkamp RK, Yee C, Adjabeng G, Elworthy TR, Tracy J, Chin E, Li J, Wang B, Bamberg JT, Stephenson R, Oshiro C, Harris SF, Ghate M, Leveque V, Najera I, Le Pogam S, Rajyaguru S, Ao-Ieong G, Alexandrova L, Larrabee S, Brandl M, Briggs A, Sukhtankar S, Farrell R, and Xu B

Subjects
Animals, Antiviral Agents chemical synthesis, Antiviral Agents pharmacokinetics, Computer Simulation, Crystallography, X-Ray, DNA-Directed RNA Polymerases metabolism, Dogs, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Humans, Quinolines chemical synthesis, Quinolines pharmacokinetics, Quinolones chemical synthesis, Quinolones pharmacology, Rats, Structure-Activity Relationship, Thiazines chemical synthesis, Thiazines pharmacology, Viral Nonstructural Proteins metabolism, Virus Replication drug effects, Antiviral Agents chemistry, DNA-Directed RNA Polymerases antagonists & inhibitors, Enzyme Inhibitors chemistry, Hepacivirus drug effects, Quinolines chemistry, Quinolones chemistry, Thiazines chemistry, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.

Published
2009
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