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

Abstract 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 EC 50 =0.47 μM against four different HRV serotypes). ©