2. Academic Validation
  3. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335)

Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335)

  • J Med Chem. 2010 Sep 9;53(17):6466-76. doi: 10.1021/jm100690x.
Montse Llinàs-Brunet 1,  Murray D Bailey,  Nathalie Goudreau,  Punit K Bhardwaj,  Josée Bordeleau,  Michael Bös,  Yves Bousquet,  Michael G Cordingley,  Jiamin Duan,  Pat Forgione,  Michel Garneau,  Elise Ghiro,  Vida Gorys,  Sylvie Goulet,  Ted Halmos,  Stephen H Kawai,  Julie Naud,  Marc-André Poupart,  Peter W White
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. montse.llinas-brunet@boehringer-ingelheim.com
PMID: 20715823 DOI: 10.1021/jm100690x
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.

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