Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
White
Peter W
PW
Boehringer Ingelheim (Canada) Ltd., 2100 Cunard St., Laval, QC, Canada. peter.white@boehringer-ingelheim.com
Llinàs-Brunet
Montse
M
Amad
Ma'an
M
Bethell
Richard C
RC
Bolger
Gordon
G
Cordingley
Michael G
MG
Duan
Jianmin
J
Garneau
Michel
M
Lagacé
Lisette
L
Thibeault
Diane
D
Kukolj
George
G
D000621:Aminoisobutyric Acids; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines; D051381:Rats; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C552340:faldaprevir
Bioorg Med Chem Lett. 1998 Jul 7;8(13):1713-8
9873421
Antimicrob Agents Chemother. 2010 Jan;54(1):305-11
19841155
Antimicrob Agents Chemother. 2006 Mar;50(3):1013-20
16495264
J Virol. 1995 Dec;69(12):7519-28
7494258
J Med Chem. 2010 Sep 9;53(17):6466-76
20715823
Science. 1989 Apr 21;244(4902):359-62
2523562
Cell. 1996 Oct 18;87(2):331-42
8861916
J Pharmacol Exp Ther. 1997 Oct;283(1):46-58
9336307
J Virol. 1993 Jul;67(7):3835-44
8389908
J Med Chem. 2006 Oct 5;49(20):6074-86
17004721
J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Jul 5;821(1):75-80
15894521
Ann Hepatol. 2009 Apr-Jun;8(2):103-12
19502651
J Hepatol. 2011 Jun;54(6):1114-22
21145839
Adv Enzyme Regul. 1984;22:27-55
6382953
J Pharm Sci. 1990 Jun;79(6):476-82
1975619
J Virol. 2002 Dec;76(24):13001-14
12438626
Hepatology. 2005 Oct;42(4):962-73
16149085
Biochem Biophys Res Commun. 2010 Jan 1;391(1):692-7
19944069
Virology. 2009 Apr 25;387(1):5-10
19304308
J Virol. 2004 Jul;78(14):7352-9
15220408
J Virol. 1998 Aug;72(8):6758-69
9658124
Nat Rev Microbiol. 2007 Jun;5(6):453-63
17487147
Antimicrob Agents Chemother. 2006 May;50(5):1813-22
16641454
Bioorg Med Chem Lett. 1998 Oct 6;8(19):2719-24
9873610
Antiviral Res. 1990 Oct-Nov;14(4-5):181-205
2088205
J Biol Chem. 2003 May 30;278(22):20374-80
12646587
Prog Med Chem. 2006;44:65-107
16697895
Nat Med. 2005 Jul;11(7):791-6
15951748
Nature. 2003 Nov 13;426(6963):186-9
14578911
Liver Int. 2009 Jan;29 Suppl 1:74-81
19207969
Biochemistry. 1998 Jun 23;37(25):8899-905
9636031
Antimicrob Agents Chemother. 2008 Dec;52(12):4432-41
18824605
Pharmacol Rev. 2006 Sep;58(3):621-81
16968952
Antimicrob Agents Chemother. 2006 Mar;50(3):899-909
16495249
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
4202581
Angew Chem Int Ed Engl. 2003 Mar 28;42(12):1356-60
12671967
Gastroenterology. 2004 Nov;127(5):1347-55
15521004
Cell. 1996 Oct 18;87(2):343-55
8861917
Hepatology. 2005 Apr;41(4):832-5
15732092
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9294-9
15939869
Antimicrob Agents Chemother. 2009 Apr;53(4):1377-85
19171797
Bioorg Med Chem Lett. 2004 Oct 4;14(19):5007-11
15341970