| Title | Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. | ||
| Author | Dragovich, P S; Prins, T J; Zhou, R; Webber, S E; Marakovits, J T; Fuhrman, S A; Patick, A K; Matthews, D A; Lee, C A; Ford, C E; Burke, B J; Rejto, P A; Hendrickson, T F; Tuntland, T; Brown, E L; Meador, J W 3rd; Ferre, R A; Harr, J E; Kosa, M B; Worland, S T | ||
| Journal | J Med Chem | Publication Year/Month | 1999-Apr |
| PMID | 10197965 | PMCID | -N/A- |
| Affiliation | 1.Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA. | ||
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 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.