title: Peptide backbone replacement of hepatitis C virus NS3 serine protease C-terminal cleavage product analogs: discovery of potent succinamide inhibitors.
abstract: A number of potent peptidic inhibitors of the NS3 protease have been described in the literature based on a substrate-based approach. In an on-going effort to reduce the peptidic character of this class of inhibitors, two novel series of analogs have been prepared in which the usual P3 amino acid residue is replaced by a succinamide fragment. This new backbone modification not only reduces the peptidic nature of traditional inhibitors but also provides new SAR opportunities for the capping group. Optimization of each of these two series resulted in inhibitors with sub-nanomolar potencies.
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: Josée
authors.initials: J
authors.lastname: Bordeleau
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Mélissa
authors.initials: M
authors.lastname: Leblanc
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lemke
authors.forename: Jeff
authors.initials: J
authors.lastname: O'Meara
authors.forename: Peter W
authors.initials: PW
authors.lastname: White
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D004285:Dogs; D006207:Half-Life; D000882:Haplorhini; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013386:Succinates / Q000737:chemistry* / Q000493:pharmacokinetics; 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: D000577:Amides; D011480:Protease Inhibitors; D013386:Succinates; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C011116:succinamide