Metal mediated protease inhibition: design and synthesis of inhibitors of the human cytomegalovirus (hCMV) protease.
A versatile synthetic route to a novel series of bis-imidazolemethanes designed to inhibit the hCMV protease has been developed and a series of potential metal binding inhibitors has been identified. In selectivity assays, the compounds were highly specific for CMV protease and showed no inhibition (IC50 > 100 microM) of other prototypical serine proteases such as trypsin, elastase, and chymotrypsin. Although the presence of free zinc ions was found to be an absolute requirement for the in vitro biological activity of this class of inhibitor, the potency of the inhibitors could not be improved beyond the micromolar level.
Dhanak
D
D
SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426-0989, USA. dash_dhanak-1@sbphrd.com
Burton
G
G
Christmann
L T
LT
Darcy
M G
MG
Elrod
K C
KC
Kaura
A
A
Keenan
R M
RM
Link
J O
JO
Peishoff
C E
CE
Shah
D H
DH
D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D008670:Metals; D008968:Molecular Conformation; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000378:metabolism
D007093:Imidazoles; D008670:Metals; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C071910:assemblin; D002918:Chymotrypsin; D010196:Pancreatic Elastase; D014357:Trypsin