Design and synthesis of monocyclic beta-lactams as mechanism-based inhibitors of human cytomegalovirus protease.
Mechanism based inhibitors of HCMV protease have been designed based on the monocyclic beta-lactam nucleus, which have been shown to acylate the viral enzyme in a time dependent manner. SAR in a series of monocyclic beta-lactam N-ureas, has defined the size and relative stereochemistry of the C-3 substituent producing a low micromolar inhibitor 17b with good aqueous stability and selectivity over the mammalian serine proteases.
Borthwick
A D
AD
Department of Enzyme Medicinal Chemistry II, Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, Herts, UK. adb3028@ggr.co.uk
Weingarten
G
G
Haley
T M
TM
Tomaszewski
M
M
Wang
W
W
Hu
Z
Z
Bedard
J
J
Jin
H
H
Yuen
L
L
Mansour
T S
TS
D004355:Drug Stability; D006801:Humans; D007536:Isomerism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D011480:Protease Inhibitors; D047090:beta-Lactams; D012697:Serine Endopeptidases; C071910:assemblin