Synthesis and antiviral activity of metabolites of rimantadine.
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.
Manchand
P S
PS
Department of Chemistry Research, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
Cerruti
R L
RL
Martin
J A
JA
Hill
C H
CH
Merrett
J H
JH
Keech
E
E
Belshe
R B
RB
Connell
E V
EV
Sim
I S
IS
D000218:Adamantane / Q000031:analogs & derivatives*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests / Q000379:methods; D015394:Molecular Structure; D012299:Rimantadine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D007202:Indicators and Reagents; D012299:Rimantadine; D000218:Adamantane