title: Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus NS3 serine protease.
abstract: Inhibitors of hepatitis C virus NS3 serine protease often incorporate a large P2 moiety to interact with the surface of the enzyme while shielding part of the catalytic triad. This feature is important in many inhibitors in order to have the necessary potency needed for efficacy. In this Letter we explore some new P2 motifs to further exploit this region of the enzyme. In a continuing effort to replace the often found 4-hydroxyproline P2 core found in the majority of inhibitors for this target, various directly attached aryl derivatives were evaluated. Of these, the 2,4-disubstituted thiazole core proved to be the most interesting. SAR around this motif has lead to compounds with Ki's in the high picomolar range and provided cellular potencies in the single digit nM range.
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. dignardbailey@aol.com
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.forename: Teddy
authors.initials: T
authors.lastname: Halmos
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lemke
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000201:enzymology*; D062105:Molecular Docking Simulation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011392:Proline; 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