J Med Chem. 2010 Sep 9;53(17):6466-76.

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

Llinàs-Brunet M, Bailey MD, Goudreau N, Bhardwaj PK, Bordeleau J, Bös M, Bousquet Y, Cordingley MG, Duan J, Forgione P, Garneau M, Ghiro E, Gorys V, Goulet S, Halmos T, Kawai SH, Naud J, Poupart MA, White PW.

Source

Department of Medicinal Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. montse.llinas-brunet@boehringer-ingelheim.com

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.

PMID:: 20715823; [PubMed - indexed for MEDLINE]

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Cited by 2 PubMed Central articles

In vitro resistance profile of the hepatitis C virus NS3 protease inhibitor BI 201335. [Antimicrob Agents Chemother. 2012]
In vitro resistance profile of the hepatitis C virus NS3 protease inhibitor BI 201335.
Lagacé L, White PW, Bousquet C, Dansereau N, Dô F, Llinas-Brunet M, Marquis M, Massariol MJ, Maurice R, Spickler C, et al. Antimicrob Agents Chemother. 2012 Jan; 56(1):569-72. Epub 2011 Oct 24.
Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease. [Antimicrob Agents Chemother. 2010]
Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, et al. Antimicrob Agents Chemother. 2010 Nov; 54(11):4611-8. Epub 2010 Sep 7.

Chemical compound information

N-((cyclopentyloxy)carbonyl)-3-methylvalyl-4-((8-bromo-7-methoxy-2-(2-((2-methylpropanoyl)amino)-1,3-thiazol-4-yl)quinolin-4-yl)oxy)-N-(1-carboxy-2-ethenylcyclopropyl)prolinamide

MW: 869.82 g/mol

MF: C₄₀H₄₉BrN₆O₉S

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