Discovery of a Potent and Selective Noncovalent Linear Inhibitor of the Hepatitis C Virus NS3 Protease (BI 201335)

• Published in: Journal of medicinal chemistry Vol. 53; no. 17; pp. 6466 - 6476
• Main Authors: Llinàs-Brunet, Montse, Bailey, Murray D, Goudreau, Nathalie, Bhardwaj, Punit K, Bordeleau, Josée, Bös, Michael, Bousquet, Yves, Cordingley, Michael G, Duan, Jiamin, Forgione, Pat, Garneau, Michel, Ghiro, Elise, Gorys, Vida, Goulet, Sylvie, Halmos, Ted, Kawai, Stephen H, Naud, Julie, Poupart, Marc-André, White, Peter W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.09.2010; Amer Chemical Soc
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Chemistry, Medicinal; Hepacivirus - enzymology; Hepacivirus - genetics; Humans; Life Sciences & Biomedicine; Male; Microsomes, Liver - metabolism; Oligopeptides - chemical synthesis; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Pharmacology & Pharmacy; Rats; Rats, Sprague-Dawley; Replicon - drug effects; Science & Technology; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - pharmacokinetics; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Viral Nonstructural Proteins - antagonists & inhibitors; MACROCYCLIC INHIBITORS; BILN-2061; REPLICATION; HUMANS; PRECLINICAL PROFILE; SERINE-PROTEASE; OPTIMIZATION; PEPTIDE-BASED INHIBITORS; SCH-503034
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100690x

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.