title: 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.
abstract: 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%).
authors.affiliation: Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., 10777 Science Center Drive, San Diego, California 92121-1111, USA. peter.dragvich@pfizer.com
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Prins
authors.forename: Ru
authors.initials: R
authors.lastname: Zhou
authors.forename: Edward L
authors.initials: EL
authors.lastname: Brown
authors.forename: Fausto C
authors.initials: FC
authors.lastname: Maldonado
authors.forename: Shella A
authors.initials: SA
authors.lastname: Fuhrman
authors.forename: Leora S
authors.initials: LS
authors.lastname: Zalman
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lee
authors.forename: Amy K
authors.initials: AK
authors.lastname: Patick
authors.forename: David A
authors.initials: DA
authors.lastname: Matthews
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Hendrickson
authors.forename: Maha B
authors.initials: MB
authors.lastname: Kosa
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Minerva R
authors.initials: MR
authors.lastname: Batugo
authors.forename: Jean-Paul R
authors.initials: JP
authors.lastname: Gleeson
authors.forename: Sylvie K
authors.initials: SK
authors.lastname: Sakata
authors.forename: Lijian
authors.initials: L
authors.lastname: Chen
authors.forename: Mark C
authors.initials: MC
authors.lastname: Guzman
authors.forename: James W
authors.initials: JW
authors.lastname: Meador
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Ferre
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Worland
mesh_terms: 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*
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D010455:Peptides; D011480:Protease Inhibitors; D011728:Pyridones; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases