GS4071 is a novel potent inhibitor of influenza neuraminidase (Ki < 1 nM) with low (< 5%) oral bioavailability in animals. An ethyl ester prodrug of GS4071, GS4104, has exhibited good oral bioavailability in rat, mouse, and dog models and is currently being developed for the treatment of influenza A and B virus infections. Since influenza virus replicates primarily in the surface epithelial cells of the respiratory tract, the ability of the prodrug to deliver GS4071 to the bronchoalveolar lining fluid (BALF) following an oral dose of GS4104 should be an important indicator of its potential efficacy. In the present study, we determined the concentration-time profiles of GS4071 in the BALF and plasma of rats following oral administration of GS4104. The BALF was sampled by bronchoalveolar lavage with endogenous urea as a dilution marker. The concentration of GS4071 in BALF reached a peak at 2 h (1 h after the plasma peak) and declined at a slower rate than plasma levels, suggesting slow clearance of drug from the lung acini. The ratios of the area-under-the-curve (AUC) values of GS4071 in BALF to those in plasma were 1.05 for AUC from 0 to 6 h (AUC(0-6)) and 1.51 for AUC(0-infinity), indicating significant penetration of the parent drug into the lower respiratory tracts of rats following oral administration of the prodrug. No unchanged GS4104 was detected in BALF.

GS-9669 is a highly optimized thumb site II nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, with a binding affinity of 1.35 nM for the genotype (GT) 1b protein. It is a selective inhibitor of HCV RNA replication, with a mean 50% effective concentration (EC 50 ) of <11 nM in genotype 1 and 5 replicon assays, but lacks useful activity against genotypes 2 to 4. The M423T mutation is readily generated clinically upon monotherapy with the thumb site II inhibitors filibuvir and lomibuvir, and it is notable that GS-9669 exhibited only a 3-fold loss in potency against this variant in the genotype 1b replicon. Rather than M423T, resistance predominantly tracks to residues R422K and L419M and residue I482L in GT 1b and 1a replicons, respectively. GS-9669 exhibited at least additive activity in combination with agents encompassing four other direct modes of action (NS3 protease, NS5A, NS5B via an alternative allosteric binding site, and NS5B nucleotide) as well as with alpha interferon or ribavirin in replicon assays. It exhibited high metabolic stability in in vitro human liver microsomal assays, which, in combination with its pharmacokinetic profiles in rat, dog, and two monkey species, is predictive of good human pharmacokinetics. GS-9669 is well suited for combination with other orally active, direct-acting antiviral agents in the treatment of genotype 1 chronic HCV infection. (This study has been registered at ClinicalTrials.gov under registration number NCT01431898.)

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