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Methods for treating drug-resistant hepatitis C virus infection with a 5,5-fused arylene or heteroarylene hepatitis C virus inhibitor

A drug resistance and disease technology, applied in antiviral agents, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of unsustainable reduction of viral load and unsatisfied

Inactive Publication Date: 2014-02-05
INDENIX PHARM LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, even with experimental regimens involving PEGylated interferon-α in combination with ribavirin, there was no sustained reduction in viral load in a significant proportion of patients (Manns et al., Lancet 2001, 358, 958-965; Fried et al. people, N. Engl. J. Med. 2002, 347, 975-982; Hadziyannis et al., Ann. Intern. Med. 2004, 140, 346-355)
Therefore, there is a clear and unmet need for the development of effective therapeutics for the treatment of HCV infection

Method used

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  • Methods for treating drug-resistant hepatitis C virus infection with a 5,5-fused arylene or heteroarylene hepatitis C virus inhibitor
  • Methods for treating drug-resistant hepatitis C virus infection with a 5,5-fused arylene or heteroarylene hepatitis C virus inhibitor
  • Methods for treating drug-resistant hepatitis C virus infection with a 5,5-fused arylene or heteroarylene hepatitis C virus inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[1040] HCV Replicon Assay

[1041] General method: in supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 110 mg / L sodium pyruvate, 1X non-essential amino acids, 100 U / mL penicillin-streptomycin, and 0.5 mg / mL G418 (Invitrogen) HuH-7 cells containing the HCV Con1 subgenotype replicon (GS4.1 cells) were cultured in Dulbecco's modified Eagle's medium (DMEM). For dose-response testing, cells were seeded into 96-well plates at a concentration of 7.5 × 10 3 cells / well, volume 50 μ L, and at 37 ° C / 5%CO 2 cultivated in. Three hours after plating, 50 μL of 10 2-fold serial dilutions of the compound (highest concentration, 75 μM) was added in the presence of 0.5% DMSO at 37 ° C / 5%CO 2 Grow the cell culture under. Alternatively, compounds were tested at a single concentration of 15 μM. In all cases, HuH-7 cells lacking the HCV replicon were used as negative controls. Cells were cultured for 72 hours in the presence of compounds, after which NS5A protein expressio...

Embodiment 1B

[1050] HCV NS5A-intergenotypic stable cells of genotypes 1a, 2a, 3a and 4a

[1051] generation of

[1052] The nucleotide sequences of the NS5A region of genotype 2a (GenBank Accession #_AB047639), genotype 3a (GenBank Accession #_D17763) and genotype 4a (GenBank Accession #_DQ418788) were synthesized by an external supplier. The NS5A region of each of these genotypes includes the first 11 amino acids of the genotype 1b protease recognition sequence, and the last 10 amino acids of genotype 1b. The NS5A gene cassette was excised with an in situ-specific restriction endonuclease and ligated to a ZS11-luciferase genotype 1b backbone with similar restriction endonuclease sites (the backbone contains the genotype 1b NS3 protease , NS4a, NS4b and NS5b coding regions). Thus, the newly constructed plasmid contained the genotype 2a-, 3a- or 4a-specific NS5A gene within the 1b-replicon.

[1053] To generate the 1a-H77NS5a intergenotype plasmid, a double restriction site was inserted ...

Embodiment 1C

[1067] Luciferase Replicon Transient Transfection Assay

[1068] General Methods: Luciferase Replicon Transient Transfection Assay Measures Test Compound Inhibition of Replication of Transiently Transfected HCV Luciferase-Carrying Wild-Type or Mutant Replicons in Healed Human Hepatoma Cells (Huh7.5) Ability. Inhibition of HCV replication was measured by quantification of luciferase protein expression. This assay has been validated using a panel of genotype 1a and 1b replicons carrying mutations known to be associated with resistance to BMS-790052. Briefly, subconfluent Huh7.5 cells were electroporated with 10 μg of HCV replicon RNA loaded with wild-type or mutant luciferase. Then, cells were seeded in 96-well opaque white plates at 3x104 cells / well in 150 μL / well and incubated at 37°C / 5% CO 2 Incubate for 4 hours. In culture medium (containing glucose, L-glutamine and sodium pyruvate, 10% fetal bovine serum, 100 IU / mL penicillin, 100 μg / ml streptomycin, 2 mM GlutaMAX and 1...

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Abstract

Provided herein are methods for treating or preventing drug-resistant hepatitis C virus infection in a subject, which comprises administering to the subject a 5,5-fused heteroarylene hepatitis C virus inhibitor compound, for example, of Formula I, IA, or IB.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 61 / 470,415, filed March 31, 2011; the disclosure of which is incorporated herein by reference in its entirety. field of invention [0003] The present application provides methods for treating or preventing drug-resistant hepatitis C virus infection in a subject comprising administering to the subject a 5,5-fused heteroarylene hepatitis C virus inhibitor compound. Background technique [0004] Hepatitis C virus (HCV) is known to cause at least 80% of post-transfusion hepatitis and a large proportion of sporadic acute hepatitis (Kuo et al., Science 1989, 244, 362-364; Thomas, Curr. Top. Microbiol. Immunol. 2000, 25-41). Preliminary evidence also suggests that HCV is present in many cases of "idiopathic" chronic hepatitis, "occult" cirrhosis, and possibly hepatocellular carcinoma unrelated to other hepatitis viruses such as hepatitis B virus (Di Beceglie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/381A61K31/407A61K31/4188A61K31/424A61K31/429A61K31/12
CPCA61K31/381A61K31/429A61K31/4188A61K31/424A61K31/407A61P1/16A61P31/14A61P35/00A61P43/00
Inventor 西里尔·B·多森大卫·杜汉克里斯托夫·克劳德·帕齐克莱尔·皮埃拉弗兰西斯-雷内·亚历山大吉尧姆·勃兰特丹尼尔·达科斯塔侯赛因·拉哈里吉恩-劳伦特·帕帕琳米歇尔·戴洛克蒂埃里·康瓦德多米尼克·苏拉劳克斯约翰·P·比列罗
Owner INDENIX PHARM LLC
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