RESUMEN
A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3-tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Amidas/química , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Antivirales/síntesis química , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos/métodos , Flúor/química , Células Hep G2/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Ácidos Fosfóricos/química , Células Vero/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/administración & dosificación , Carbamatos , Línea Celular/efectos de los fármacos , Línea Celular/virología , Técnicas de Química Sintética , Chlorocebus aethiops , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Hepacivirus/genética , Humanos , Imidazoles/farmacología , Terapia Molecular Dirigida , Mutación , Pirrolidinas , Relación Estructura-Actividad , Valina/análogos & derivados , Células Vero/efectos de los fármacos , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Traditional methods for general drug discovery typically include evaluating random compound libraries for activity in relevant cell-free or cell-based assays. Success in antiviral development has emerged from the discovery of more focused libraries that provide clues about structure activity relationships. Combining these with more recent approaches including structural biology and computational modeling can work efficiently to hasten discovery of active molecules, but that is not enough. There are issues related to biology, toxicology, pharmacology, and metabolism that have to be addressed before a hit compound becomes nominated for clinical development. The objective of gaining early preclinical knowledge is to reduce the risk of failure in Phases 1, 2, and 3, leading to the goal of approved drugs that benefit the infected individual. This review uses hepatitis C virus (HCV), for which we still do not have an ideal therapeutic modality, as an example of the multidisciplinary efforts needed to discover new antiviral drugs for the benefit of humanity.