223526-37-2Relevant articles and documents
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 8. Pharmacological optimization of orally bioavailable 2-pyridone-containing peptidomimetics
Dragovich, Peter S.,Prins, Thomas J.,Zhou, Ru,Johnson, Theodore O.,Hua, Ye,Luu, Hiep T.,Sakata, Sylvie K.,Brown, Edward L.,Maldonado, Fausto C.,Tuntland, Tove,Lee, Caroline A.,Fuhrman, Shella A.,Zalman, Leora S.,Patick, Amy K.,Matthews, David A.,Wu, Ellen Y.,Guo, Ming,Borer, Bennett C.,Nayyar, Naresh K.,Moran, Terence,Chen, Lijian,Rejto, Paul A.,Rose, Peter W.,Guzman, Mark C.,Dovalsantos, Elena Z.,Lee, Steven,McGee, Kevin,Mohajeri, Michael,Liese, Andreas,Tao, Junhua,Kosa, Maha B.,Liu, Bo,Batugo, Minerva R.,Gleeson, Jean-Paul R.,Wu, Zhen Ping,Liu, Jia,Meador III, James W.,Ferre, Rose Ann
, p. 4572 - 4585 (2007/10/03)
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 P 2 substituent present in the peptidomimetic portion of the inhibitors. The pharmacokineties 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 (kobs/[Il 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).
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements
Dragovich, Peter S.,Prins, Thomas J.,Zhou, Ru,Webber, Stephen E.,Marakovits, Joseph T.,Fuhrman, Shella A.,Patick, Amy K.,Matthews, David A.,Lee, Caroline A.,Ford, Clifford E.,Burke, Benjamin J.,Rejto, Paul A.,Hendrickson, Thomas F.,Tuntland, Tove,Brown, Edward L.,Meador III, James W.,Ferre, Rose Ann,Harr, James E. V.,Kosa, Maha B.,Worland, Stephen T.
, p. 1213 - 1224 (2007/10/03)
The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 ? 0.10 μM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.
