Solid-phase synthesis of irreversible human rhinovirus 3C protease inhibitors. Part 1: Optimization of tripeptides incorporating N-terminal amides

The optimization of a series of irreversible human rhinovirus (HRV) 3C prot ease (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-te rminal ethyl propenoate Michael acceptor. Examination of approximately 500 compounds with varying N-terminal amides utilizing solid-phase synthesis an d high-throughput assay techniques is described along with the solution pha se preparation of several highly active molecules. A tripeptide Michael acc eptor containing an N-terminal amide derived from 5-methylisoxazole-3-carbo xylic acid is shown to exhibit potent, irreversible anti-3CP activity (k(ob s)/[I] = 260,000 M-1 s(-1); type-14 3CP) and broad-spectrum antirhinoviral properties (average EC50 = 0.47 mu M against four different HRV serotypes). (C) 1999 Elsevier Science Ltd. All rights reserved.