ABSTRACT
Since its first use in the steroid field in the late 1950s, the use of fluorine in medicinal chemistry has become commonplace, with the small electronegative fluorine atom being a key part of the medicinal chemist's repertoire of substitutions used to modulate all aspects of molecular properties including potency, physical chemistry and pharmacokinetics. This review will highlight the special nature of fluorine, drawing from a survey of marketed fluorinated pharmaceuticals and the medicinal chemistry literature, to illustrate key concepts exploited by medicinal chemists in their attempts to optimize drug molecules. Some of the potential pitfalls in the use of fluorine will also be highlighted.
Subject(s)
Chemistry, Pharmaceutical , Fluorine , Animals , Fluorine/chemistry , Humans , Molecular Conformation , SolubilityABSTRACT
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 effectsABSTRACT
The discovery of 4'-azidocytidine (3) (R1479) (J. Biol. Chem. 2006, 281, 3793; Bioorg. Med. Chem. Lett. 2007, 17, 2570) as a potent inhibitor of RNA synthesis by NS5B (EC(50) = 1.28 microM), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of several monofluoro and difluoro derivatives of 4'-azidocytidine. The most potent compounds in this series were 4'-azido-2'-deoxy-2',2'-difluorocytidine and 4'-azido-2'-deoxy-2'-fluoroarabinocytidine with antiviral EC(50) of 66 nM and 24 nM in the HCV replicon system, respectively. The structure-activity relationships within this series were discussed, which led to the discovery of these novel nucleoside analogues with the most potent compound, showing more than a 50-fold increase in antiviral potency as compared to 4'-azidocytidine (3).
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Azides/chemical synthesis , Azides/pharmacology , Deoxycytidine/analogs & derivatives , Drug Design , Hepacivirus/physiology , Virus Replication/drug effects , Antiviral Agents/chemistry , Azides/chemistry , Cell Line, Tumor , Deoxycytidine/chemical synthesis , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Hepacivirus/drug effects , HumansABSTRACT
4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.17 microM in the genotype 1b subgenomic replicon system. The structure-activity relationships within this series of nucleoside analogues are discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cytarabine/analogs & derivatives , Drug Design , Hepacivirus/drug effects , Virus Replication/drug effects , Antiviral Agents/chemistry , Cell Line , Cytarabine/chemical synthesis , Cytarabine/chemistry , Cytarabine/pharmacology , Inhibitory Concentration 50 , Molecular StructureABSTRACT
Isoquinoline-based non-nucleoside inhibitors of HCV NS5b RNA-dependent RNA-polymerase are described. The synthesis and structure-activity relationships are detailed, along with enzyme and cellular activity.
Subject(s)
Enzyme Inhibitors/pharmacology , Isoquinolines/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Isoquinolines/chemistry , Models, Molecular , Structure-Activity RelationshipABSTRACT
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Pyridazines , Reverse Transcriptase Inhibitors , Animals , Dogs , Drug Resistance, Viral/drug effects , Inhibitory Concentration 50 , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Novel non-nucleoside inhibitors of HIV-RT that contain pyridazinone isosteres were prepared, and a series of triazolinones were found to be potent inhibitors of HIV replication. These compounds were active against several NNRTI-resistant virus strains. Pharmacokinetic studies indicated that inhibitor 7e has good bioavailability in rats. Several fragments of inhibitor 7c were prepared, and the binding of these compounds to HIV-RT was analyzed by surface plasmon resonance spectroscopy.
Subject(s)
Anti-HIV Agents , Pyridazines , Reverse Transcriptase Inhibitors , Triazoles , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Combinatorial Chemistry Techniques , Drug Resistance, Viral/drug effects , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Surface Plasmon Resonance , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.
