Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 8. Pharmacological optimization of orally bioavailable 2-pyridone-containing peptidomimetics.
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).
Dragovich
Peter S
PS
Pfizer Global Research and Development-La Jolla, 10777 Science Center Drive, San Diego, CA 92121-1111, USA. peter.dragovich@pfizer.com
Prins
Thomas J
TJ
Zhou
Ru
R
Johnson
Theodore O
TO
Hua
Ye
Y
Luu
Hiep T
HT
Sakata
Sylvie K
SK
Brown
Edward L
EL
Maldonado
Fausto C
FC
Tuntland
Tove
T
Lee
Caroline A
CA
Fuhrman
Shella A
SA
Zalman
Leora S
LS
Patick
Amy K
AK
Matthews
David A
DA
Wu
Ellen Y
EY
Guo
Ming
M
Borer
Bennett C
BC
Nayyar
Naresh K
NK
Moran
Terence
T
Chen
Lijian
L
Rejto
Paul A
PA
Rose
Peter W
PW
Guzman
Mark C
MC
Dovalsantos
Elena Z
EZ
Lee
Steven
S
McGee
Kevin
K
Mohajeri
Michael
M
Liese
Andreas
A
Tao
Junhua
J
Kosa
Maha B
MB
Liu
Bo
B
Batugo
Minerva R
MR
Gleeson
Jean-Paul R
JP
Wu
Zhen Ping
ZP
Liu
Jia
J
Meador
James W
JW
Ferre
Rose Ann
RA
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*
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