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1.
Bioorg Med Chem Lett ; 19(19): 5652-6, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19709881

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.


Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Thiazoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , 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
2.
Bioorg Med Chem Lett ; 19(19): 5648-51, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19700319

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.


Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Pyrrolidinones/chemistry , Thiazines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , 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
3.
Bioorg Med Chem Lett ; 19(13): 3642-6, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19457662

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.


Subject(s)
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 , 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
4.
Bioorg Med Chem Lett ; 19(13): 3637-41, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19447623

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.


Subject(s)
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 , 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
6.
J Am Chem Soc ; 127(1): 225-35, 2005 Jan 12.
Article in English | MEDLINE | ID: mdl-15631472

ABSTRACT

Detailed experimental approaches toward the pentacyclic Stemona alkaloids tuberostemonine and didehydrotuberostemonine and the close analogue 13-epituberostemonine are described. The syntheses originate with a hydroindolinone derivative that can be obtained on a large scale in a single step from carbobenzoxy-protected l-tyrosine. Highlights of the conversion of this hydroindolinone to the target structures are the three-fold use of ruthenium catalysts, first in azepine ring-closing metathesis and then in alkene isomerization and cross-metathesis propenyl-vinyl exchange, as well as the stereoselective attachment of a gamma-butyrolactone ring to a tetracycle core structure by use of a lithiated asymmetric bicyclo[3.2.1]octane (ABO) ortho ester. Structural analysis by density functional theory (DFT) methods revealed that the ease of oxidation of the natural product is likely due to the conformational preferences of the pyrrolidine and the fused cyclohexane rings.


Subject(s)
Alkaloids/chemical synthesis , Lactones/chemical synthesis , Pyrrolidines/chemical synthesis , Indoles/chemical synthesis , Models, Molecular , Stemonaceae/chemistry
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