Potent beta-lactam inhibitors of human cytomegalovirus protease.
A series of novel monobactam inhibitors of human cytomegalovirus (HCMV) protease has been described that possess a heterocyclic thiomethyl side chain at C-4. Changes to the heterocycle did not significantly change the inhibitory activity of these compounds in an enzymatic assay, although improvements in solubility and cell culture activity were noted. A number of permutations between C-4 substitutions and N-1 derivatives led to the identification of several beta-lactams with antiviral activity in a plaque reduction assay. N-methyl thiotetrazole-containing compounds were found to be the most potent inhibitors in the enzymatic assay.
Yoakim
C
C
Bio-Méga Research Division, Boehringer Ingelheim (Canada), Laval, Québec. cyoakim@bio-mega.boehringer-ingelheim.ca
Ogilvie
W W
WW
Cameron
D R
DR
Chabot
C
C
Grand-Maître
C
C
Guse
I
I
Haché
B
B
Kawai
S
S
Naud
J
J
O'Meara
J A
JA
Plante
R
R
Déziel
R
R
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology*; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013777:Tetrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives; D014764:Viral Proteins / Q000378:metabolism; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000494:pharmacology
D000998:Antiviral Agents; D015842:Serine Proteinase Inhibitors; D013777:Tetrazoles; D014764:Viral Proteins; D047090:beta-Lactams; D014508:Urea