Discovery of benzimidazole-diamide finger loop (Thumb Pocket I) allosteric inhibitors of HCV NS5B polymerase: Implementing parallel synthesis for rapid linker optimization.

Bioorganic & Medicinal Chemistry Letters
Sylvie GouletPierre L Beaulieu

Abstract

Previously described SAR of benzimidazole-based non-nucleoside finger loop (Thumb Pocket I) inhibitors of HCV NS5B polymerase was expanded. Prospecting studies using parallel synthesis techniques allowed the rapid identification of novel cinnamic acid right-hand sides that provide renewed opportunities for further optimization of these inhibitors. Novel diamide derivatives such as 44 exhibited comparable potency (enzymatic and cell-based HCV replicon) as previously described tryptophan-based inhibitors but physicochemical properties (e.g., aqueous solubility and lipophilicity) have been improved, resulting in molecules with reduced off-target liabilities (CYP inhibition) and increased metabolic stability.

References

Jun 25, 2005·Current Drug Metabolism·Amit S KalgutkarShawn P Harriman
Aug 19, 2005·Nature·Raffaele De Francesco, Giovanni Migliaccio
Nov 1, 2007·Nature Reviews. Drug Discovery·Paul D Leeson, Brian Springthorpe

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Citations

Mar 8, 2011·Journal of Medicinal Chemistry·Jih Ru HwuJohan Neyts
Dec 22, 2011·Journal of Medicinal Chemistry·Michael J SofiaBruce S Ross
Oct 30, 2014·Chemical Biology & Drug Design·Rangappa S KeriBhari Mallanna Nagaraja
Feb 23, 2011·Future Medicinal Chemistry·Kunal KumarIwao Ojima
Oct 15, 2010·Journal of the American Chemical Society·Steven R LaPlantePierre L Beaulieu
Oct 4, 2012·Bioorganic & Medicinal Chemistry·Yogita Bansal, Om Silakari

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