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1.
J Med Chem ; 61(20): 9218-9228, 2018 10 25.
Article in English | MEDLINE | ID: mdl-30265808

ABSTRACT

MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the synthesis and antiviral evaluation of carbocyclic derivatives. Synthesized analogs were evaluated for their antiviral activity, and the corresponding triphosphates were synthesized and evaluated in a biochemical assay. 4'-Ethynyl-G derivative (±)-29 displayed a promising IC50 of 33 nM in a hPBMC cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC50 of 324 nM in a biochemical RT-polymerase assay. Improved TP anabolite delivery resulting in improved in vitro potency was achieved by preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying a significantly improved IC50 of 3.0 nM, paving the way for new directions for this novel class of nucleoside analogs.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Deoxyadenosines/chemical synthesis , Deoxyadenosines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Cell Line , Chemistry Techniques, Synthetic , Deoxyadenosines/metabolism , Deoxyadenosines/pharmacokinetics , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Conformation , Rats , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacokinetics , Tissue Distribution
2.
Bioorg Med Chem Lett ; 27(18): 4323-4330, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28835346

ABSTRACT

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.


Subject(s)
Antiviral Agents/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Uridine Monophosphate/analogs & derivatives , Uridine/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , DNA-Directed RNA Polymerases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Liver/drug effects , Liver/virology , Mice , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Uridine/chemical synthesis , Uridine/chemistry , Uridine Monophosphate/chemical synthesis , Uridine Monophosphate/chemistry , Uridine Monophosphate/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
3.
Bioorg Med Chem Lett ; 27(11): 2634-2640, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28416131

ABSTRACT

Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.


Subject(s)
Antiviral Agents/chemistry , Hepacivirus/enzymology , Lactams/chemistry , Organophosphorus Compounds/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Regulation , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Genotype , Half-Life , Haplorhini , Hepacivirus/genetics , Hepacivirus/physiology , Humans , Lactams/pharmacology , Mice , Molecular Dynamics Simulation , Organophosphorus Compounds/pharmacology , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
4.
Bioorg Med Chem Lett ; 26(18): 4536-4541, 2016 09 15.
Article in English | MEDLINE | ID: mdl-27520942

ABSTRACT

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.


Subject(s)
Antiviral Agents/pharmacology , Genotype , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Site , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Crystallography, X-Ray , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
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