Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements.
The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.
Dragovich
P S
PS
Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA.
Prins
T J
TJ
Zhou
R
R
Webber
S E
SE
Marakovits
J T
JT
Fuhrman
S A
SA
Patick
A K
AK
Matthews
D A
DA
Lee
C A
CA
Ford
C E
CE
Burke
B J
BJ
Rejto
P A
PA
Hendrickson
T F
TF
Tuntland
T
T
Brown
E L
EL
Meador
J W
JW
Ferre
R A
RA
Harr
J E
JE
Kosa
M B
MB
Worland
S T
ST
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005973:Glutamine / Q000737:chemistry*; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012229:Rhinovirus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives; D014764:Viral Proteins
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D007555:Isoxazoles; D007769:Lactams; D009842:Oligopeptides; D011760:Pyrrolidinones; D014764:Viral Proteins; D005973:Glutamine; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D014633:Valine; C118874:rupintrivir