beta-Lactam derivatives as inhibitors of human cytomegalovirus protease.
The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the beta-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.
Bio-Méga Research Division, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Québec H7S 2G5, Canada. cyoakim@bio-mega.boehringer-ingelheim.ca
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C
Yoakim
W W
WW
Ogilvie
D R
DR
Cameron
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C
Chabot
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Guse
B
B
Haché
J
J
Naud
J A
JA
O'Meara
R
R
Plante
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Déziel
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D002461:Cell Line, Transformed; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D015842:Serine Proteinase Inhibitors; D047090:beta-Lactams; D014508:Urea; D012697:Serine Endopeptidases; C071910:assemblin