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Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 8. Pharmacological Optimization of Orally Bioavailable 2-Pyridone-Containing Peptidomimetics
Ist Teil von
Journal of medicinal chemistry, 2003-10, Vol.46 (21), p.4572-4585
Ort / Verlag
Washington, DC: American Chemical Society
Erscheinungsjahr
2003
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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 α,β-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 P2 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 α,β-unsaturated ethyl ester fragment and either an ethyl or propargyl P2 moiety displayed the most promising combination of 3C enzyme inhibition (k obs/[I] 170 000−223 000 M-1 s-1), antiviral activity (EC50 = 0.047−0.058 μM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248−0.682 μM; 7 h CM-monkey plasma levels = 0.057−0.896 μM).