Design and synthesis of irreversible depsipeptidyl human rhinovirus 3C protease inhibitors.
Novel tripeptidyl C-terminal Michael acceptors with an ester replacement of the P(2)-P(3) amide bond were investigated as irreversible inhibitors of the human rhinovirus (HRV) 3C protease (3CP). When screened against HRV serotype-14 the best compound was shown to have very good 3CP inhibition (k(obs)/[I]=270,000M(-1)s(-1)) and potent in vitro antiviral activity (EC(50)=7.0nM).
Webber
S E
SE
Pfizer Global Research and Development, La Jolla, 3565 General Atomics Court, San Diego, CA 92121, USA. swebber@anadyspharma.com
Marakovits
J T
JT
Dragovich
P S
PS
Prins
T J
TJ
Zhou
R
R
Fuhrman
S A
SA
Patick
A K
AK
Matthews
D A
DA
Lee
C A
CA
Srinivasan
B
B
Moran
T
T
Ford
C E
CE
Brothers
M A
MA
Harr
J E
JE
Meador
J W
JW
Ferre
R A
RA
Worland
S T
ST
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012229:Rhinovirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D010455:Peptides; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases