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4 results on '"Fell JB"'

1. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides.

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, Li J, Wang B, Bamberg JT, Harris SF, Wong A, Leveque VJ, Najera I, Le Pogam S, Rajyaguru S, Ao-Ieong G, Alexandrova L, Larrabee S, Brandl M, Briggs A, Sukhtankar S, and Farrell R

Subjects
Animals, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Binding Sites, Crystallography, X-Ray, Haplorhini, Rats, Structure-Activity Relationship, Thiazoles chemical synthesis, Thiazoles pharmacokinetics, Viral Nonstructural Proteins metabolism, Antiviral Agents chemical synthesis, Hepacivirus drug effects, Thiazoles chemistry, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.

Published
2009
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2. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: synthesis and optimization studies of benzothiazine-substituted tetramic acids.

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, Zhao J, Elworthy TR, Tracy J, Chin E, Li J, Lui A, Wang B, Oshiro C, Harris SF, Ghate M, Leveque VJ, Najera I, Le Pogam S, Rajyaguru S, Ao-Ieong G, Alexandrova L, Fitch B, Brandl M, Masjedizadeh M, Wu SY, de Keczer S, and Voronin T

Subjects
Animals, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Binding Sites, Crystallography, X-Ray, Pyrrolidinones chemical synthesis, Pyrrolidinones pharmacokinetics, Rats, Structure-Activity Relationship, Viral Nonstructural Proteins metabolism, Antiviral Agents chemical synthesis, Hepacivirus drug effects, Pyrrolidinones chemistry, Thiazines chemistry, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.

Published
2009
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3. 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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4. 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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