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1.
Bioorg Med Chem Lett ; 22(11): 3747-50, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22542020

ABSTRACT

Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase.


Subject(s)
Protease Inhibitors/chemistry , Uracil/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Substitution , Genotype , Hepacivirus/drug effects , Hepacivirus/enzymology , Kinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Transcription Initiation Site , Uracil/chemical synthesis , Uracil/chemistry , Uracil/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
2.
Bioorg Med Chem Lett ; 21(6): 1876-9, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21316235

ABSTRACT

A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.


Subject(s)
Benzothiadiazines/pharmacology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Benzothiadiazines/chemistry , Hepacivirus/enzymology , Hepacivirus/physiology , Protease Inhibitors/chemistry , Virus Replication
3.
J Med Chem ; 52(10): 3174-83, 2009 May 28.
Article in English | MEDLINE | ID: mdl-19402666

ABSTRACT

Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.


Subject(s)
Benzothiadiazines/chemical synthesis , Benzothiadiazines/pharmacology , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzothiadiazines/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Genotype , Hepacivirus/genetics , Liver/metabolism , Microbial Sensitivity Tests , Rats , Structure-Activity Relationship , Tissue Distribution
4.
J Med Chem ; 52(6): 1659-69, 2009 Mar 26.
Article in English | MEDLINE | ID: mdl-19226162

ABSTRACT

The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.


Subject(s)
Benzothiadiazines/chemical synthesis , Benzothiadiazines/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Animals , Benzothiadiazines/pharmacokinetics , Biological Availability , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Magnetic Resonance Spectroscopy , Rats , Spectrometry, Mass, Electrospray Ionization
5.
Bioorg Med Chem Lett ; 18(14): 3887-90, 2008 Jul 15.
Article in English | MEDLINE | ID: mdl-18599294

ABSTRACT

4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Chemistry, Pharmaceutical/methods , Drug Design , Genotype , Infusions, Intravenous , Inhibitory Concentration 50 , Models, Chemical , Rats , Viral Nonstructural Proteins/genetics
6.
Bioorg Med Chem Lett ; 18(11): 3173-7, 2008 Jun 01.
Article in English | MEDLINE | ID: mdl-18479921

ABSTRACT

Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Salicylamides/chemical synthesis , Salicylamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Combinatorial Chemistry Techniques , Drug Design , Humans , Molecular Structure , Salicylamides/chemistry , Structure-Activity Relationship
8.
Biochemistry ; 45(38): 11312-23, 2006 Sep 26.
Article in English | MEDLINE | ID: mdl-16981691

ABSTRACT

Little is known about the mechanism of HCV polymerase-catalyzed nucleotide incorporation and the individual steps employed by this enzyme during a catalytic cycle. In this paper, we applied various biochemical tools and examined the mechanism of polymerase catalysis. We found that formation of a productive RNA-enzyme complex is the slowest step followed by RNA dissociation and initiation of primer strand synthesis. Various groups have reported several classes of small molecule inhibitors of hepatitis C virus NS5B polymerase; however, the mechanism of inhibition for many of these inhibitors is not clear. We undertook a series of detailed mechanistic studies to characterize the mechanisms of inhibition for these HCV polymerase inhibitors. We found that the diketoacid derivatives competitively bind to the elongation NTP pocket in the active site and inhibit both the initiation and elongation steps of polymerization. While both benzimidazoles and benzothiadiazines are noncompetitive with respect to the active site elongation NTP pocket, benzothiadiazine compounds competitively bind to the initiation pocket in the active site and inhibit only the initiation step of de novo RNA polymerization. The benzimidazoles bind to the thumb allosteric pocket and inhibit the conformational changes during RNA synthesis. We also observed a cross interaction between the thumb allosteric pocket and the initiation pocket using inhibitor-inhibitor cross competition studies. This information will be very important in designing combination therapies using two small molecule drugs to treat hepatitis C virus.


Subject(s)
Benzimidazoles/pharmacology , Benzothiadiazines/pharmacology , Polymers/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Benzimidazoles/chemistry , Benzothiadiazines/chemistry , Electrophoresis , Heparin/metabolism , Humans , Kinetics , Protein Binding , Protein Structure, Secondary , RNA, Viral/metabolism , Substrate Specificity , Templates, Genetic , Time Factors , Viral Nonstructural Proteins/chemistry
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