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Bioorg Med Chem Lett
; 25(12): 2505-9, 2015 Jun 15.
Artigo
em Inglês
| MEDLINE
| ID: mdl-25980910
RESUMO
Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs.
Assuntos
Inibidores Enzimáticos/química , Neuraminidase/antagonistas & inibidores , Pró-Fármacos/química , Ácidos Siálicos/química , Proteínas Virais/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Camundongos , Neuraminidase/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ácidos Siálicos/síntese química , Ácidos Siálicos/farmacocinética , Proteínas Virais/metabolismo
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