RESUMEN
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.
Asunto(s)
Antivirales/farmacología , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Uridina Monofosfato/análogos & derivados , Uridina/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , ARN Polimerasas Dirigidas por ADN/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Hepatocitos/efectos de los fármacos , Hepatocitos/virología , Humanos , Hígado/efectos de los fármacos , Hígado/virología , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Uridina/síntesis química , Uridina/química , Uridina Monofosfato/síntesis química , Uridina Monofosfato/química , Uridina Monofosfato/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
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
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.
Asunto(s)
Antivirales/farmacología , Genotipo , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitio Alostérico , Antivirales/química , Antivirales/metabolismo , Cristalografía por Rayos X , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as a seven-membered ring sugar moiety, namely 9-(5-deoxy-beta-D-allo-septanosyl)-adenine, is reported. This compound was synthesized in 14 steps from the commercially available D-glycero-D-gulo-1,4-lactone. When evaluated in cell culture experiments against a broad range of viruses, it did not exhibit any significant antiviral effect or cytotoxicity.
Asunto(s)
Nucleósidos/química , Nucleósidos/síntesis química , Oligosacáridos/química , Oligosacáridos/síntesis química , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Flavivirus/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Modelos Químicos , Estructura Molecular , Nucleósidos/farmacología , Pestivirus/efectos de los fármacosRESUMEN
In the search for inhibitors of the replication of RNA viruses, including hepatitis C virus (HCV), the hitherto unknown 4'-C-azidomethyl-beta-D-ribofuranosyl nucleosides of the five naturally occurring nucleic acid bases have been synthesized and their antiviral properties examined. These 4'-C-branched nucleosides were stereospecifically prepared by glycosylation of purine and pyrimidine aglycons with a suitable peracylated 4-C-azidomethyl-D-pentofuranose sugar, followed by removal of the protecting groups. The prepared compounds were tested for their activity against several viruses, but they did not show an antiviral effect.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Nucleósidos de Purina/química , Nucleósidos de Purina/farmacología , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Virus ARN/efectos de los fármacos , Antivirales/síntesis química , Nucleósidos de Purina/síntesis química , Nucleósidos de Pirimidina/síntesis químicaRESUMEN
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as the sugar moiety was synthesized and evaluated as a potential inhibitor of several virus replication.