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Use of hif alpha stabilizers for enhancing erythropoiesis

A technology of erythropoietin and red blood cells, which is applied in the application field of HIFα stabilizers that enhance red blood cell production, and can solve the problems of weakened iron utilization

Active Publication Date: 2006-08-09
FIBROGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Functional iron deficiency is often seen in healthy individuals with apparently normal or even increased iron stores but impaired iron availability as measured by, for example, low levels of percent transferrin saturation

Method used

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  • Use of hif alpha stabilizers for enhancing erythropoiesis
  • Use of hif alpha stabilizers for enhancing erythropoiesis
  • Use of hif alpha stabilizers for enhancing erythropoiesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0263] Embodiment 1: Overcoming the inhibitory effect of TNF-α on EPO generation

[0264] Hep3B cells were treated with various concentrations (0, 0.4, 2, 10 ng / ml) of TNF-α in the absence or presence of compound A or compound B for three days. Secreted EPO levels were determined using a commercially available ELISA kit (R&D Systems, catalog number DEP00). In the absence of compound, treatment of Hep3B cells with TNF-[alpha] decreased EPO production in a dose-dependent manner. Hep3B cells treated with various concentrations of Compound A (Fig. IA) or Compound B (Fig. IB) in the absence of TNF-[alpha] showed a dose-dependent increase in EPO production. Addition of either of these compounds in the presence of TNF-[alpha] significantly reduced the inhibitory effect of TNF-[alpha] on EPO production. Overcoming of the inhibitory effect of TNF-[alpha] on EPO production by prolyl hydroxylase inhibition was observed in the presence of low (eg 0.4 ng / ml) and high (eg 10 ng / ml) concen...

Embodiment 2

[0268] Example 2: Overcoming the inhibitory effect of IL-1β on EPO production

[0269] Hep3B cells were treated with various concentrations (0, 0.4, 2, 10 ng / ml) of IL-1β in the absence or presence of compound A or compound B for 3 days. Secreted EPO levels were determined using a commercially available ELISA kit (R&D Systems, catalog number DEP00). Treatment of Hep3B cells with IL-1β decreased EPO production in a dose-dependent manner in the absence of compound. In the absence of IL-1β with various concentrations of compound A ( Figure 3A ) or compound B ( Figure 3B ) treated Hep3B cells showed a dose-dependent increase in EPO production. Addition of either compound in the presence of IL-1[beta] significantly reduced the inhibitory effect of IL-1[beta] on EPO production. Overcoming of IL-1β inhibition of EPO production by prolyl hydroxylase inhibition was observed in the presence of low (eg 0.4 ng / ml) and high (eg 10 ng / ml) concentrations of IL-1β. Thus, the inhibitory ...

Embodiment 3

[0273] Example 3: Inhibition of TNF-alpha-induced VCAM-1 expression

[0274] Adhesion of endothelial cells to lymphocytes occurs in part through expression of vascular cell adhesion molecule (VCAM)-1 by endothelial cells. VCAM-1 expression in endothelial cells is induced by various inflammatory cytokines such as TNF-α. To study the effect of HIF prolyl hydroxylase inhibition on TNF-α-induced VCAM-1 expression, HUVEC (human umbilical vein endothelial cells) were treated with TNF in the absence or presence of various concentrations of compound B or compound C - Alpha stimulation for 1 day. VCAM expression was then measured.

[0275] like Figure 5As shown, TNF-α (1 ng / ml) induced VCAM-1 expression in HUVEC cells. However, addition of Compound B or Compound C to TNF-α-stimulated cells resulted in a dose-dependent inhibition of TNF-α-induced VCAM-1 expression. This data demonstrates that the methods and compounds of the invention are effective at reducing VCAM-1 expression as...

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PUM

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Abstract

The present invention relates to methods and compounds for regulating or enhancing erythropoiesis and iron metabolism, and for treating or preventing iron deficiency and anemia of chronic disease.

Description

[0001] This application claims serial numbers 60 / 476,704 filed June 6, 2003, 60 / 566,488 filed April 29, 2004, and 60 / 566,237 filed April 29, 2004 , and priority of US Provisional Application Serial No. 60 / 569,797 filed May 10, 2004. All of the above applications are incorporated herein by reference in their entirety. field of invention [0002] The present invention relates to methods and compounds for regulating or enhancing erythropoiesis and iron metabolism, treating or preventing iron deficiency and anemia of chronic disease. Background of the invention [0003] Anemia generally refers to any abnormality in hemoglobin or red blood cells that results in a decreased level of oxygen in the blood. Anemia can also occur in association with chronic diseases such as chronic infection, neoplastic disease, chronic inflammation including lesions followed by inflammatory suppression of the bone marrow. Anemia of chronic disease is one of the most common syndromes in medicine. ...

Claims

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Application Information

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IPC IPC(8): A61K31/00A61K31/395A61K31/165A61P7/06
CPCA61K31/00A61K31/165A61K31/395C07C275/40C07D217/24
Inventor 斯蒂芬·J.·克劳斯克里斯托弗·J.·莫林奥克斯托马斯·B.·内夫福尔克马尔·京茨勒-普卡尔英格丽德·兰瑟特莫帕罗布克托德·W.·西利罗伯特·C.·斯蒂芬森
Owner FIBROGEN INC
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