RESUMO
We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Guanosina Monofosfato/análogos & derivados , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , AMP Desaminase/metabolismo , Amidas/química , Amidas/metabolismo , Antivirais/química , Linhagem Celular Tumoral , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Guanosina Monofosfato/química , Guanosina Monofosfato/farmacologia , Hepacivirus/fisiologia , Hepatite C/tratamento farmacológico , Humanos , Hidrólise , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Nucleosídeos/farmacologia , Ácidos Fosfóricos/química , Ácidos Fosfóricos/metabolismo , Fosforilação , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: The reticulocyte maturation process is an ideal model for the study of biochemical alterations seen during final stage of erythropoiesis under disease conditions. In this study, determined whether type 2 diabetes has any effect on membrane lipids and protein-bound carbohydrates during the maturation of reticulocytes to erythrocytes. SUBJECTS AND METHODS: Lipids (cholesterol and phospholipids) and protein-bound carbohydrates (hexose, hexosamine and sialic acid) were extracted and estimated in plasma, membrane of reticulocytes and erythrocytes from 20 treated but uncontrolled type 2 diabetic volunteers and age matched controls. RESULTS: Plasma, membranes of reticulocytes and erythrocytes of diabetics showed increase in cholesterol (35.7%, 8.7% and 16.4%); phospholipids (43.4%, 18.8% and 8.2%); hexose (34.1%, 19.3% and 8.2%) and decrease in hexosamine (11.9%, 7.3% and 14.7%); and sialic acid (34.1%, 19.3% and 32.0%) compared to controls. As reticulocytes matured to erythrocytes, cholesterol, phospholipids, hexosamine and sialic acid levels were decreased; C/P ratio and hexose levels were increased in both controls and diabetics. However, these alterations were more intensified in diabetics. CONCLUSION: These alterations in diabetic patients may indicate the existence of one or both of the following conditions: acceleration of maturation processes and/or decreased red blood cell life span.