A-315675 is a novel,
pyrrolidine-based compound that was evaluated in this study for its ability to inhibit A and B strain influenza virus neuraminidases in
enzyme assays and influenza virus replication in cell culture.
A-315675 effectively inhibited
influenza A N1, N2, and N9 and B strain neuraminidases with inhibitor constant (K(i)) values between 0.024 and 0.31 nM. These values were comparable to or lower than the K(i) values measured for
oseltamivir carboxylate (
GS4071),
zanamivir, and
BCX-1812, except for the N1
enzymes that were found to be the most sensitive to
BCX-1812. The time-dependent inhibition of
neuraminidase catalytic activity observed with
A-315675 is likely due to its very low rate of dissociation from the active site of
neuraminidase. The half times for dissociation of
A-315675 from B/Memphis/3/89 and A/Tokyo/3/67 (H3N2) influenza virus neuraminidases of 10 to 12 h are significantly slower than the half times measured for
oseltamivir carboxylate (33 to 60 min).
A-315675 inhibited the replication of several laboratory strains of influenza virus in cell culture with potencies that were comparable or superior to those for
oseltamivir carboxylate and
BCX-1812, except for the A/H1N1 viruses that were found to be two- to fourfold more susceptible to
BCX-1812.
A-315675 and
oseltamivir carboxylate exhibited comparable potencies against a panel of A/H1N1 and A/H3N2 influenza virus clinical isolates, but
A-315675 was found to be significantly more potent than
oseltamivir carboxylate against the B strain isolates. The favorable in vitro results relative to other clinically effective agents provide strong support for the further investigation of
A-315675 as a potential
therapy for influenza virus
infections.