Article ID Journal Published Year Pages File Type
1377753 Bioorganic & Medicinal Chemistry Letters 2007 7 Pages PDF
Abstract

Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-bromo-2-fluoro-phenyl)pteridin-4-ylamino]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36 with a replicon EC50 of 64 nM, associated with a selective kinase inhibitory profile for human JNK kinases 2 and 3 as well as VEGFR-1, 2, and 3 kinases. Moreover, 36 showed an advantageous PK profile in mice. Experiments performed using different replicon constructs suggest that this series of kinase inhibitors might mediate their effect through the HCV non-structural protein 5A (NS5A).

Graphical abstractNovel pteridines that act as HCV inhibitors are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide

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Physical Sciences and Engineering Chemistry Organic Chemistry
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