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Stabilization of hypoxia inducible factor (HIF) alpha

A hypoxia-inducible factor, stable technology, applied to the field of compounds that can be used in these methods

Inactive Publication Date: 2010-03-10
FIBROGEN (CHINA) MEDICAL TECHNOLOGY DEVELOPMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Concomitant stabilization with other drugs such as digoxin, diuretics, amrinone, beta-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, but none of the treatments directly target ischemia and tissue damage caused by hypoxia

Method used

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  • Stabilization of hypoxia inducible factor (HIF) alpha
  • Stabilization of hypoxia inducible factor (HIF) alpha
  • Stabilization of hypoxia inducible factor (HIF) alpha

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0252] Example 1 Stabilization of HIFα in vitro cells

[0253] Adenovirus-denatured fetal kidney epithelial cells (293A), cervical epithelial adenocarcinoma cells (HeLa), liver cancer cells (Hep3B), foreskin fibroblasts (HFF), breast epithelial carcinoma cells (MCF7), vein-bearing endothelial cells ( HUVEC), microvascular endothelial cells (HMEC-1), umbilical squamous cell carcinoma cells (SCC-25), lung fibroblasts (HLF), vein endothelial cells (AG10774B) tissues (see, e.g., American Type Culture Collection, ManassaVA : Qbiogene, Carlsbad CA) human cells were planted in 35mm culture dish respectively, at 37 ℃, 20% O 2 , 5%CO 2 Cultured in the environment, the medium is as follows: HeLa cells in Dulbecco's modified Eagle medium (DMEM), 2% fetal bovine serum (FBS); HFF and HLF cells in DMEM, 10% FBS; 293A cells in DMEM, 5% FBS; HUVEC and AG10774B cells in endothelial growth medium (EGM-2: BioWhittaker, Inc., Walkersville MD); HMEC-1 in RPMI 1640, 10% FBS; Hep3B cells in Minima...

Embodiment 2

[0257] Embodiment 2: oxygen consumption effect

[0258] Oxygen-sensing cell culture dishes (BD Bioscience, Bedford MA) contained a ruthenium complex that was more fluorescent under low oxygen conditions. Thus, if oxygen-consuming cells are present in the dish, the fluorescent readout signal is enhanced, which skews the equilibrium toward a state of low oxygen saturation and high fluorescence. Compounds that stabilize HIF by inhibiting hydroxylation are expected to reduce oxygen consumption, ie, oxygen consumption by hydroxylation itself, and / or shift cellular metabolism from aerobic to anaerobic energy.

[0259] Culture adenovirus-denatured fetal kidney epithelial cells (293A) or cervical epithelial adenocarcinoma cells (HeLa) (American type strain collection), and keep them at 37°C and 10% CO 2 Conditions were confluent in medium (high glucose DMEM (Mediatech, Inc., Herndon VA), 1% penicillin / streptomycin mixture (Mediatech), 1% baby calf serum). Cells were collected and re...

Embodiment 3

[0262] Example 3: Expression of HIF-regulated genes in vitro

[0263] Vascular endothelial growth factor (VEGF) was analyzed on the opsonizing medium collected from the cell culture fluid prepared as in Example 1 using a QUANTIKINE immunoassay device (R&D) according to the manufacturer's instructions. Such as Figure 4 As shown in A, foreskin fibroblasts (HFF), adenovirus The expression of VEGF in denatured fetal kidney epithelial cells (293A) and liver cancer cells (Hep3B) decreased ( Figure 4 A). Values ​​on the Y axis represent the log of the fold induction relative to the reference 2 value, such that a value of 1 represents a 2-fold induction.

[0264] Alternatively, at 37 °C and 10% CO 2 Human cells derived from adenovirus-denatured fetal kidney epithelial cells (293A) were cultured in DMEM, 5% FBS, 1% penicillin-streptomycin. After 48 hours, the cells were collected and pooled in a 35mm culture dish. The medium used was conventional medium, and the medium was chan...

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Abstract

The present invention relates to methods of stabilizing the alpha subunit of hypoxia inducible factor (HIF). The invention further relates to methods of preventing, pretreating, or treating conditions associated with HIF, including ischemic and hypoxic conditions. Compounds for use in these methods are also provided.

Description

[0001] This application is a divisional application of an invention patent application with an application date of December 6, 2002, an application number of 02824098.7, and an invention title of "stabilization of hypoxia-inducible factor (HIF) alpha". [0002] This invention claims U.S. Provisional Patent Application 60 / 337082, filed December 6, 2001, U.S. Provisional Patent Application 60 / 359,683, filed February 25, 2002, U.S. Provisional Patent Application, filed January 16, 2002 60 / 349,659 and US Provisional Patent Application 60 / 386,488, filed June 5, 2002, each of which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to methods of stabilizing the alpha subunit of hypoxia inducible factor (HIF), and to compounds useful in these methods. Background of the invention [0004] An early response to tissue hypoxia is the production of hypoxia-inducible factor (HIF), a basic helix-loop-helix (bHLH) PAS (Per / Arnt / Si...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P3/10A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61P11/00A61P17/02A61P25/00A61P43/00
Inventor V·古恩泽勒-普卡尔T·B·尼夫Q·王M·P·阿兰德L·A·弗利平V·古恩泽勒－普卡尔
Owner FIBROGEN (CHINA) MEDICAL TECHNOLOGY DEVELOPMENT CO LTD
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