title: Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.
abstract: Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1-P3 cyclization, which gave products with inhibition constants in the nanomolar range ( approximately 75nM).
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Ortqvist
authors.forename: Shane D
authors.initials: SD
authors.lastname: Peterson
authors.forename: Eva
authors.initials: E
authors.lastname: Kerblom
authors.forename: Thomas
authors.initials: T
authors.lastname: Gossas
authors.forename: Yogesh A
authors.initials: YA
authors.lastname: Sabnis
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fransson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindeberg
authors.forename: U
authors.initials: U
authors.lastname: Helena Danielson
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D005998:Glycine; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C027797:phenylglycine chloride; C008852:2-phenylglycine