4mkb
Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with inhibitor 14 (N-(4-{(E)-2-[3-tert-butyl-2-methoxy-5-(3-oxo-2,3-dihydropyridazin-4-yl)phenyl]ethenyl}phenyl)methanesulfonamide)
Structural highlights
Publication Abstract from PubMedHepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor in combination with pegylated interferon with ribavirin, represents a major advancement in recent years, an unmet medical need still exists to develop treatment modalities that improve upon both efficacy and tolerability. Towards those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to move towards interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition which has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Optimization addressed issues of potency, early safety and pharmacokinetics to provide a clinical candidate in fluoropyridone 19. Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B.,Schoenfeld RC, Bourdet DL, Brameld KA, Chin E, de Vicente J, Fung A, Harris SF, Lee E, Le Pogam S, Leveque V, Li J, Lui AS, Najera I, Rajyaguru S, Sangi M, Steiner S, Talamas FX, Taygerly JP, Zhao J J Med Chem. 2013 Sep 27. PMID:24069953[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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