title: Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335).
abstract: C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.
authors: Department of Medicinal Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. montse.llinas-brunet@boehringer-ingelheim.com
authors: Montse
authors: M
authors: Llinàs-Brunet
authors: Murray D
authors: MD
authors: Bailey
authors: Nathalie
authors: N
authors: Goudreau
authors: Punit K
authors: PK
authors: Bhardwaj
authors: Josée
authors: J
authors: Bordeleau
authors: Michael
authors: M
authors: Bös
authors: Yves
authors: Y
authors: Bousquet
authors: Michael G
authors: MG
authors: Cordingley
authors: Jiamin
authors: J
authors: Duan
authors: Pat
authors: P
authors: Forgione
authors: Michel
authors: M
authors: Garneau
authors: Elise
authors: E
authors: Ghiro
authors: Vida
authors: V
authors: Gorys
authors: Sylvie
authors: S
authors: Goulet
authors: Ted
authors: T
authors: Halmos
authors: Stephen H
authors: SH
authors: Kawai
authors: Julie
authors: J
authors: Naud
authors: Marc-André
authors: MA
authors: Poupart
authors: Peter W
authors: PW
authors: White
mesh_terms: D000621:Aminoisobutyric Acids; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives; D011804:Quinolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D012093:Replicon / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D007930:Leucine; D009842:Oligopeptides; D011392:Proline; D011804:Quinolines; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C552340:faldaprevir