title: 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 EC50 = 0.47 microM against four different HRV serotypes).
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: R
authors.initials: R
authors.lastname: Zhou
authors.forename: D J
authors.initials: DJ
authors.lastname: Skalitzky
authors.forename: S A
authors.initials: SA
authors.lastname: Fuhrman
authors.forename: A K
authors.initials: AK
authors.lastname: Patick
authors.forename: C E
authors.initials: CE
authors.lastname: Ford
authors.forename: J W
authors.initials: JW
authors.lastname: Meador
authors.forename: S T
authors.initials: ST
authors.lastname: Worland
mesh_terms: D000086042:3C Viral Proteases; D000577:Amides / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D014764:Viral Proteins
chemical_list: D000577:Amides; D010455:Peptides; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases