Substituted benzamide inhibitors of human rhinovirus 3C protease: structure-based design, synthesis, and biological evaluation.
A series of nonpeptide benzamide-containing inhibitors of human rhinovirus (HRV) 3C protease was identified using structure-based design. The design, synthesis, and biological evaluation of these inhibitors are reported. A Michael acceptor was combined with a benzamide core mimicking the P1 recognition element of the natural 3CP substrate. alpha,beta-Unsaturated cinnamate esters irreversibly inhibited the 3CP and displayed antiviral activity (EC(50) 0.60 microM, HRV-16 infected H1-HeLa cells). On the basis of cocrystal structure information, a library of substituted benzamide derivatives was prepared using parallel synthesis on solid support. A 1.9 A cocrystal structure of a benzamide inhibitor in complex with the 3CP revealed a binding mode similar to that initially modeled wherein covalent attachment of the nucleophilic cysteine residue is observed. Unsaturated ketones displayed potent reversible inhibition but were inactive in the cellular antiviral assay and were found to react with nucleophilic thiols such as DTT.
Reich
S H
SH
Agouron Pharmaceuticals Inc., 3565 General Atomics Court, San Diego, California 92121, USA.
Johnson
T
T
Wallace
M B
MB
Kephart
S E
SE
Fuhrman
S A
SA
Worland
S T
ST
Matthews
D A
DA
Hendrickson
T F
TF
Chan
F
F
Meador
J
J
Ferre
R A
RA
Brown
E L
EL
DeLisle
D M
DM
Patick
A K
AK
Binford
S L
SL
Ford
C E
CE
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D011487:Protein Conformation; D012229:Rhinovirus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins
D000998:Antiviral Agents; D001549:Benzamides; D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases