Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 6. Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics.
The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I] > 500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) = <0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).
Dragovich
Peter S
PS
Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., 10777 Science Center Drive, San Diego, California 92121-1111, USA. peter.dragvich@pfizer.com
Prins
Thomas J
TJ
Zhou
Ru
R
Brown
Edward L
EL
Maldonado
Fausto C
FC
Fuhrman
Shella A
SA
Zalman
Leora S
LS
Tuntland
Tove
T
Lee
Caroline A
CA
Patick
Amy K
AK
Matthews
David A
DA
Hendrickson
Thomas F
TF
Kosa
Maha B
MB
Liu
Bo
B
Batugo
Minerva R
MR
Gleeson
Jean-Paul R
JP
Sakata
Sylvie K
SK
Chen
Lijian
L
Guzman
Mark C
MC
Meador
James W
JW
Ferre
Rose Ann
RA
Worland
Stephen T
ST
D000086042:3C Viral Proteases; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012229:Rhinovirus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D008024:Ligands; D010455:Peptides; D011480:Protease Inhibitors; D011728:Pyridones; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases