2. Academic Validation
  3. Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism

Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism

  • J Med Chem. 2014 Mar 13;57(5):1964-75. doi: 10.1021/jm401337x.
Martin Leivers 1,  John F Miller,  Stephanie A Chan,  Ryan Lauchli,  Sebastian Liehr,  Wenyan Mo,  Tony Ton,  Elizabeth M Turner,  Michael Youngman,  J Greg Falls,  Susan Long,  Amanda Mathis,  Jill Walker
Affiliations

Affiliation

  • 1 GlaxoSmithKline Research & Development , 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
PMID: 24224729 DOI: 10.1021/jm401337x
Abstract

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.

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