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Methods and compositions for treating flaviviruses, pestiviruses and hepacivirus

A compound, an independent technology, applied in the direction of antiviral agents, active ingredients of carbohydrates, sugar derivatives, etc.

Inactive Publication Date: 2007-11-14
IDENIX (CAYMAN) LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Human pestiviruses have not been as extensively characterized as animal pestiviruses

Method used

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  • Methods and compositions for treating flaviviruses, pestiviruses and hepacivirus
  • Methods and compositions for treating flaviviruses, pestiviruses and hepacivirus
  • Methods and compositions for treating flaviviruses, pestiviruses and hepacivirus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0295] Phosphorylation assay for the conversion of nucleosides to activated triphosphates

[0296] To determine the cellular metabolism of compounds, HepG2 cells were obtained from the American Type Culture Collection (Rockville, MD) and made at 225 cm 2 Grow in tissue culture flasks in minimal essential medium supplemented with non-essential amino acids, 1% penicillin-streptomycin. The medium was refreshed every three days and the cells were subcultured weekly. After stripping the adherent monolayer of cells by exposing to 30 mL of insulin-EDTA for 10 min and successively washing three times with medium, confluent HepG2 cells were incubated at 2.5 × 10 6 Cells / well density were seeded in 6-well plates and exposed to 10 μM [ 3 H] labeled active compound (500 dpm / pmol). Keep cells at 37 °C and 5% CO 2 in the atmosphere. At selected time points, cells were washed three times with ice-cold phosphate-buffered saline (PBS). Intracellular active compounds and their respective ...

Embodiment 2

[0298] Bioavailability assay in macaques

[0299] Within one week before the start of the study, rhesus monkeys were surgically implanted with chronic venous catheters and subcutaneous venous access ports (VAP) to facilitate blood collection, and underwent physical examination, including histological and serum chemistry evaluation, and recorded body weight. Each monkey (total of six) received approximately 250 μCi by intravenous bolus (3 monkeys, IV), or by oral gavage (3 monkeys, PO) 3 H activity, wherein the dose level of the active compound per dose is 10 mg / kg, and the dose concentration is 5 mg / mL. Each dosing syringe was weighed prior to dosing to determine by weight the amount of dosage form administered. At indicated intervals (approximately 18-0 hours pre-dose, 0-4, 4-8, and 8-12 hours post-dose), urine samples were collected via capture plates and processed. Collected similarly via chronic venous catheter and VAP, or if chronic venous catheter approach is not possi...

Embodiment 3

[0301]Myelotoxicity Assay

[0302] Human bone marrow cells were collected from normal healthy volunteers according to the aforementioned Sommadossi J-P, Carlisle R. "Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoieticprogenitor cells in vitro"Antimicrobial Agent sand Chemotherapy 1987;31:452-454; and Sommadossi J-P, Schinazi RF, Chu CK, Xie M-Y."Comparison of cytotoxicity of the(-)-and(+)-enantiomer of 2′,3′- Mononuclear populations were isolated by Fico-Pak gradient centrifugation as described in dideoxy-3'-thiacytidine inorganic human bone marrow progenitor cells" Biochemical Pharmacology 1992;44:1921-1925. CFU-GM and BFU-E medium assays were performed using double layer soft agar or methylcellulose methods. Drugs were diluted in tissue culture medium and filtered. at 37°C and 5% CO 2 After 14 to 18 days in a humid air atmosphere, colonies larger than 50 cells were counted using an inverse microscope. Results...

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Abstract

A method and composition for treating a host infected with flavivirus, pestivirus or hepacivirus comprising administering an effective flavivirus, pestivirus or hepacivirus treatment amount of a described base-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 613,085, filed September 24,2004. field of invention [0003] The invention belongs to the field of medicinal chemistry, in particular to compounds, methods and compositions for treating flavivirus, pestivirus and hepatitis virus, especially hepatitis C virus infection. Background of the invention [0004] Pestiviruses, flaviviruses, and hepatitis C viruses belong to the family Flaviviridae. Pestiviruses include bovine viral diarrhea virus (BVDV), typical swine fever virus (CSFV, also known as swine cholera virus), and sheep border disease virus (BDV) (Moennig, V. et al., Adv. Vir. Res. .1992, 41, 53-98). Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause severe economic losses worldwide. BVDV causes bovine mucosal disease and is of obvious economic importance to the farming industry (Meyers, G. and Thiel,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/70C07H19/048C07H19/00
CPCC07H19/048C07H19/00A61K36/00A61K45/06A61K31/7076A61P31/12A61P31/14A61K2300/00A61K31/70
Inventor 吉恩-皮埃尔·索莫多西吉尔斯·格索林理查德·斯托勒詹姆士·伊根
Owner IDENIX (CAYMAN) LTD
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