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 effectsABSTRACT
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/metabolismABSTRACT
Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.
Subject(s)
Anti-HIV Agents/pharmacology , Drug Discovery , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , HIV-1/enzymology , Indoles/pharmacology , Phosphinic Acids/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Cell Line , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , HIV Reverse Transcriptase/metabolism , Hepatocytes/chemistry , Hepatocytes/metabolism , Humans , Indoles/chemical synthesis , Indoles/chemistry , Macaca fascicularis , Male , Models, Molecular , Molecular Structure , Phosphinic Acids/chemical synthesis , Phosphinic Acids/chemistry , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of 3-aryl-phospho-indole (API) non-nucleoside reverse transcriptase inhibitors of HIV-1 was developed. Chemical variation in the phosphorus linker led to the discovery of 3-phenyl-methyl-phosphinate-2-carboxamide 14, which possessed excellent potency against wild-type HIV-1 as well as viruses bearing K103N and Y181C single mutants in the reverse transcriptase gene. Chiral separation of the enantiomers showed that only R enantiomer retained the activity. The pharmacokinetic, solubility, and metabolic properties of 14 were assessed.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Reverse Transcriptase/metabolism , Indoles/chemical synthesis , Phosphinic Acids/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Animals , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Cell Line , Dogs , Drug Resistance, Viral , HIV Reverse Transcriptase/genetics , Haplorhini , Hepatocytes/metabolism , Humans , Indoles/pharmacokinetics , Indoles/pharmacology , Models, Molecular , Mutation , Phosphinic Acids/pharmacokinetics , Phosphinic Acids/pharmacology , Rats , Reverse Transcriptase Inhibitors/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacology , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), and three flaviviruses, namely, yellow fever virus, West Nile virus, and dengue-2 virus. However, pharmacokinetic studies revealed that 2'-C-methylcytidine suffers from a low oral bioavailability. To overcome this limitation, we have synthesized the 3'-O-l-valinyl ester derivative (dihydrochloride form, valopicitabine, NM283) of 2'-C-methylcytidine. We detail herein for the first time the chemical synthesis and physicochemical characteristics of this anti-HCV prodrug candidate, as well as a comparative study of its pharmacokinetic parameters with those of its parent nucleoside analogue, 2'-C-methylcytidine.
