RESUMEN
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.
Asunto(s)
Antivirales/química , Hepacivirus/enzimología , Lactamas/química , Compuestos Organofosforados/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Antivirales/farmacología , Sitios de Unión , Cristalografía por Rayos X , Genotipo , Semivida , Haplorrinos , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , Lactamas/farmacología , Ratones , Simulación de Dinámica Molecular , Compuestos Organofosforados/farmacología , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Ribonucleoside analogs possessing a ß-methyl substituent at the 2'-position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure-activity relationships of several phosphoramidate diester derivatives of 2'-C-methylguanosine (2'-MeG). CONCLUSION: The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Descubrimiento de Drogas , Guanosina Monofosfato/análogos & derivados , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Guanosina Monofosfato/síntesis química , Guanosina Monofosfato/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
A 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), "PHEEPA" [(2-pyrimidinyl-2-(2-hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase.
Asunto(s)
Materiales Biomiméticos/química , Materiales Biomiméticos/síntesis química , Técnicas de Química Sintética/métodos , Nucleósidos/química , Organofosfonatos/química , Organofosfonatos/síntesis química , Pirimidinas/química , Pirimidinas/síntesis química , Timidina Fosforilasa/químicaRESUMEN
Several thieno[3,4-d]pyrimidine derivatives, including four hitherto unknown 2',3'-dideoxy- and 2',3'-dideoxy-2',3'-didehydro-C-nucleoside analogues of adenosine and inosine have been synthesized. When evaluated in cell culture experiments against human immunodeficiency virus, none of the tested compounds exhibited any significant antiviral effect, while two of them showed some cytotoxicity.
Asunto(s)
Adenosina/análogos & derivados , Antivirales/síntesis química , Antivirales/farmacología , Inosina/análogos & derivados , Pirimidinas/síntesis química , Pirimidinas/farmacología , Antivirales/química , VIH/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pirimidinas/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
9-Deazaguanosine and the alpha and beta anomers of its 2'-C-methyl counter part, have been synthesized and evaluated against a broad range of RNA viruses, including hepatitis C virus.
Asunto(s)
Antivirales/síntesis química , Guanosina/análogos & derivados , Antivirales/química , Antivirales/farmacología , Flavivirus/efectos de los fármacos , Guanosina/síntesis química , Guanosina/química , Guanosina/farmacología , Hepacivirus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain 'natural' pyrimidine bases, but possess a beta-methyl substituent at the 2'-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA+), single-stranded negative (ssRNA-) or double-stranded (dsRNA), revealed potent activities for D-2'-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5'-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2'-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.
Asunto(s)
Antivirales/farmacología , Nucleósidos de Pirimidina/farmacología , Virus ARN/efectos de los fármacos , Virus ARN/fisiología , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Línea Celular , Cricetinae , Perros , Haplorrinos , Humanos , Estructura Molecular , Nucleósidos de Pirimidina/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Citidina/análogos & derivados , Hepacivirus/efectos de los fármacos , Profármacos/síntesis química , Profármacos/farmacocinética , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/farmacocinética , Animales , Disponibilidad Biológica , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Citidina/química , Citosol/metabolismo , Humanos , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Unión Proteica , Ratas , Ratas Sprague-Dawley , SolubilidadRESUMEN
The "unnatural" l-nucleoside beta-l-2'-deoxythymidine (L-dT) is a potent, specific, and selective inhibitor of the replication of hepatitis B virus (HBV), which is currently in Phase III clinical trials. This unit describes, in detail, a semi-large-scale synthesis of l-dT. This convenient methodology produces l-dT in six steps starting with l-ribose and ending with a satisfactory overall yield of l-dT, and may be applied to other 2'-deoxynucleosides, incorporating different heterocyclic bases.
Asunto(s)
Antivirales/síntesis química , Timidina/síntesis química , Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/fisiología , Timidina/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
beta-L-2'-Deoxycytidine (beta-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well N4-derivatization with an N,N-(dimethylamino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, beta-L-dC.