RESUMO
By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Piridazinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Piridazinas/química , Piridazinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
In our search for improved therapeutic agents against HCV we synthesized 7-deaza-7-ethynyl-2'-C-methyladenosine (1) and its 2'-deoxy-2'-fluoro analogue 2. The corresponding nucleoside triphosphates were efficient chain terminators of the HCV NS5b polymerase with IC(50)'s of 0.75 microM and 0.4 microM respectively. However, only the ribo-nucleoside 1 exhibited activity in a Huh7 cell based replicon assay with an EC(50) of 0.09 microM. In order to overcome the lack of activity of the fluoro analogue 2 we synthesised several phosphoroamidate prodrugs.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Tubercidina/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Tubercidina/síntese química , Tubercidina/química , Tubercidina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
Tripeptide libraries of the type Fmoc(W/F)XF were screened for binding to the large subunit of mouse ribonucleotide reductase (mRR), using a new, affinity chromatography method. A high-affinity tripeptide, FmocWFF, was found that inhibited mRR activity with a K(i) equal to that of AcFTLDADF, the heptapeptide corresponding to the C-terminus of the small subunit of mRR.