title: Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 8. Pharmacological optimization of orally bioavailable 2-pyridone-containing peptidomimetics.
abstract: The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).
authors.affiliation: Pfizer Global Research and Development-La Jolla, 10777 Science Center Drive, San Diego, CA 92121-1111, USA. peter.dragovich@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: Theodore O
authors.initials: TO
authors.lastname: Johnson
authors.forename: Ye
authors.initials: Y
authors.lastname: Hua
authors.forename: Hiep T
authors.initials: HT
authors.lastname: Luu
authors.forename: Sylvie K
authors.initials: SK
authors.lastname: Sakata
authors.forename: Edward L
authors.initials: EL
authors.lastname: Brown
authors.forename: Fausto C
authors.initials: FC
authors.lastname: Maldonado
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lee
authors.forename: Shella A
authors.initials: SA
authors.lastname: Fuhrman
authors.forename: Leora S
authors.initials: LS
authors.lastname: Zalman
authors.forename: Amy K
authors.initials: AK
authors.lastname: Patick
authors.forename: David A
authors.initials: DA
authors.lastname: Matthews
authors.forename: Ellen Y
authors.initials: EY
authors.lastname: Wu
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.forename: Bennett C
authors.initials: BC
authors.lastname: Borer
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Nayyar
authors.forename: Terence
authors.initials: T
authors.lastname: Moran
authors.forename: Lijian
authors.initials: L
authors.lastname: Chen
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.forename: Peter W
authors.initials: PW
authors.lastname: Rose
authors.forename: Mark C
authors.initials: MC
authors.lastname: Guzman
authors.forename: Elena Z
authors.initials: EZ
authors.lastname: Dovalsantos
authors.forename: Steven
authors.initials: S
authors.lastname: Lee
authors.forename: Kevin
authors.initials: K
authors.lastname: McGee
authors.forename: Michael
authors.initials: M
authors.lastname: Mohajeri
authors.forename: Andreas
authors.initials: A
authors.lastname: Liese
authors.forename: Junhua
authors.initials: J
authors.lastname: Tao
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: Zhen Ping
authors.initials: ZP
authors.lastname: Wu
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: James W
authors.initials: JW
authors.lastname: Meador
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Ferre
mesh_terms: D000086042:3C Viral Proteases; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004285:Dogs; D015195:Drug Design; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D012229:Rhinovirus / Q000187:drug effects / Q000201:enzymology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D001798:Blood Proteins; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D011728:Pyridones; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases