HCV NS5B is an RNA-dependent RNA polymerase that plays an essential role in HCV replication.  Research at Abbott has identified aryluracil analogs that are potent inhibitors of NS5B activity, and as such represent a novel structural class of HCV antivirals.  Early hit-to-lead efforts identified a series of arylamide-substituted analogs that gave >1000-fold improvement in activity in both enzyme inhibition and replicon assays relative to initially identified high-throughput screening hits.  However, these potent inhibitors suffered from low oral bioavailability in rat due to poor physical properties.  Medicinal chemistry efforts to find a suitable replacement for the amide linkage resulted in the identification of trans-stilbene analogs that provided further improvement in both enzyme and replicon inhibition assays (genotype 1), as well as good plasma exposures in rat following oral dosing.  Lead optimization identified a compound that gave a serum-adjusted EC50 = 2 nM in both 1a and 1b replicon assays, good oral bioavailability in both rat (F = 44%) and dog (86%), and high liver/plasma ratios following oral dosing in rat (L/P = 71 at 12 h) and dog (L/P = 11 at 12 h).  Following the successful completion of GLP toxicology studies in multiple species, this compound was designated ABT-072.  The structure of this compound and the medicinal chemistry enabling its potency and favorable PK will be presented.  A summary of preclinical efficacy studies and Phase I and Phase IIa clinical findings will be included.

Discovery of ABT-072, a potent inhibitor of HCV NS5B polymerase in clinical trials

244th National Meeting (2012)

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