199006-31-0Relevant articles and documents
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
Dragovich, Peter S.,Prins, Thomas J.,Zhou, Ru,Brown, Edward L.,Maldonado, Fausto C.,Fuhrman, Shella A.,Zalman, Leora S.,Tuntland, Tove,Lee, Caroline A.,Patick, Amy K.,Matthews, David A.,Hendrickson, Thomas F.,Kosa, Maha B.,Liu, Bo,Batugo, Minerva R.,Gleeson, Jean-Paul R.,Sakata, Sylvie K.,Chen, Lijian,Guzman, Mark C.,Meador III, James W.,Ferre, Rose Ann,Worland, Stephen T.
, p. 1607 - 1623 (2007/10/03)
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 (kobs/[I] > 500 000 M-1 s-1) that function as potent antirhinoviral agents (EC50 = 0.05 μM) 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%).