GSK2485852 is a previously disclosed potent boronic acid inhibitor of the HCV RNA-dependent RNA polymerase with excellent bioavailability in man.  We recently reported the pharmacokinetics and antiviral profile of GSK2485852 in chronically infected Hepatitis C patients.  Single dose pharmacokinetics in Hepatitis C patients with GSK2485852 showed rapid metabolism affording high concentrations of two long-lived metabolites including a low molecule weight boronic acid fragment.  Identification and characterization of the metabolites from our FTIH trials led to a rational re-design of our inhibitors affording second generation boron-containing HCV RNA-dependent RNA polymerase inhibitor GSK2878175.  We report the first time disclosure and chemical synthesis of GSK2878175, in addition to a full preclinical antiviral and pharmacokinetic characterization and FTIH pharmacokinetic profile in healthy adults.  GSK2878175 shows pan genotype broad-spectrum inhibition of HCV replicons, a high barrier to resistance, a distinct binding mode with HCV polymerase co-crystals, and low clearance and high bioavailability across preclinical species.

First structural disclosure, discovery, preclinical characterization, and FTIH pharmacokinetics for GSK2878175, a second generation boron-based inhibitor of the HCV RNA-dependent RNA polymerase

249th National Meeting (2015)

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