Title | Solid-phase synthesis of irreversible human rhinovirus 3C protease inhibitors. Part 1: Optimization of tripeptides incorporating N-terminal amides. | ||
Author | Dragovich, P S; Zhou, R; Skalitzky, D J; Fuhrman, S A; Patick, A K; Ford, C E; Meador, J W 3rd; Worland, S T | ||
Journal | Bioorg Med Chem | Publication Year/Month | 1999-Apr |
PMID | 10353638 | PMCID | -N/A- |
Affiliation | 1.Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. |
The optimization of a series of irreversible human rhinovirus (HRV) 3C protease (3CP) inhibitors is described. These inhibitors are comprised of an L-Leu-L-Phe-L-Gln tripeptide containing an N-terminal amide moiety and a C-terminal ethyl propenoate Michael acceptor. Examination of approximately 500 compounds with varying N-terminal amides utilizing solid-phase synthesis and high-throughput assay techniques is described along with the solution phase preparation of several highly active molecules. A tripeptide Michael acceptor containing an N-terminal amide derived from 5-methylisoxazole-3-carboxylic acid is shown to exhibit potent, irreversible anti-3CP activity (k(obs)/[I] = 260,000 M(-1) s(-1); type-14 3CP) and broad-spectrum antirhinoviral properties (average EC50 = 0.47 microM against four different HRV serotypes).