Synthesis and antiviral activity of metabolites of rimantadine.
Manchand PS, Cerruti RL, Martin JA, Hill CH, Merrett JH, Keech E, Belshe RB, Connell EV, Sim IS.
The hydroxy metabolites of rimantadine (3-5) were synthesized and compared to amantadine (1) and rimantadine (2) for their ability to inhibit the replication of influenza viruses in vitro. All three metabolites were inhibitory to wild-type influenza A viruses (H3N2 and H1N1). In particular, 2-hydroxyrimantadine (3) showed similar activity to amantadine, but the 3- and 4-hydroxy metabolites (4 and 5, respectively), both of which are found in rimantadine-treated patients, showed only modest inhibitory activity. A rimantadine-resistant isolate of influenza A virus exhibited cross-resistance to amantadine and to each of the metabolites 3-5. None of the compounds were effective against influenza B virus.