Inhibitors of inflammatory gene activity and cholesterol biosynthesis

A gene and inflammation technology, applied in the field of inhibitors of inflammatory gene activity and cholesterol biosynthesis

Inactive Publication Date: 2005-09-28
WYETH HOLDINGS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] In addition, there has been no previous approach to effectively, safely, and inexpensively identify agents that effectively inhibit SHP or FXR activity in inflammatory gene pathways and / or cholesterol biosynthesis pathways, or develop products based on them that could be effectively targeted to patients Disorders associated with inflammatory disease expression and / or cholesterol biosynthesis in

Method used

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  • Inhibitors of inflammatory gene activity and cholesterol biosynthesis
  • Inhibitors of inflammatory gene activity and cholesterol biosynthesis
  • Inhibitors of inflammatory gene activity and cholesterol biosynthesis

Examples

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preparation example Construction

[0302] During the preparation of such modifications, the hydropathic index of amino acids can be considered. The importance of the hydropathic index of amino acids in conferring reciprocal biological functions on polypeptides is generally understood in the art (Kyte & Doolittle, 1982). It is well known that certain amino acids can be substituted by other amino acids having a similar hydropathic index or score and still result in a polypeptide having similar biological activity. Each amino acid has been assigned a hydropathic index based on its hydrophobic and charge properties. Those indices are listed in parentheses after each amino acid as follows: Isoleucine (+4.5); Valine (+4.2); Leucine (+3.8); Phenylalanine (+2.8); Cysteine Acid / Cysteine ​​(+2.5); Methionine (+1.9); Alanine (+1.8); Glycine (-0.4); Threonine (-0.7); Serine (-0.8); Tryptophan Acid (-0.9); Tyrosine (-1.3); Proline (-1.6); Histidine (-3.2); Glutamic acid (-3.5); Glutamine (-3.5); Aspartic acid (-3.5); asp...

Embodiment 1-

[0359] Example 1 - Ethinyl estradiol inhibits IL-1β-induced gene expression in mouse liver

[0360] The study was based on the observation that the incidence of cardiovascular disease in women is extremely low before menopause, but then rises sharply after menopause. Numerous studies have shown that hormone replacement therapy can reduce the incidence of cardiovascular disease in postmenopausal women. Although estrogen had a beneficial effect on lipid profile, changes in lipid profile only partly explained the reduction in incidence. Inflammation is an important part of the atherosclerotic process. To investigate the ability of estrogen to suppress inflammation in vivo, ovariectomized female C57BL / 6 mice were treated with vehicle or ethinyl estradiol (EE) for four days, followed by IL-1β for 1 hour. Microarray analysis of liver RNA revealed that IL-1β induced approximately 100 genes. EE treatment suppressed the induction of approximately one-third of these genes. This ef...

Embodiment 2

[0377] Example 2 - Regulate the expression of SHP

[0378] Several experiments were performed to study the regulation of SHP expression as follows. Referring to FIG. 9 , the regulation of SHP expression by ERα in mouse liver was investigated. By subcutaneous injection of vehicle, 10 μg / kg / day of E2, 10 μg / kg / day of E2+5 mg / kg / day of ICI182780, 5 mg / kg / day of tamoxifen or 5 mg / kg / day of PPT, Ovariectomized wild-type ErαERβ double knockout ERαKO or ERβKO mice were processed. Hepatic expression of SHP was monitored by real-time PCR, corrected for expression of GAPDH. In WT animals, E2, tamoxifen, and PPT, a selective antagonist of ERα, all induced SHP mRNA levels. ICI182780 inhibits this induction. E2 fails to induce SHP expression in ERαKO or ERβKO mice. In ERβKO mice, the basal expression of SHP was enhanced, but E2 still induced the expression of SHP. At the same time, these results indicated that the induction of SHP by estrogen in mouse liver was mainly mediated by E...

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Abstract

Methods of identifying agents effective as inhibitors of short heterodimer protein (SHP) and farnesoid X receptor (FXR) and promoters, cell lines and vectors used in said methods. Methods of preparing and using the agents effective as inhibitors of short heterodimer protein (SHP), including methods of using same to prevent and / or treat a condition associated with inflammatory gene activity and / or cholesterol biosynthesis in a subject. Agents effective as inhibitors of short heterodimer protein (SHP) and farnesoid X receptor (FXR) and compositions comprising same, including compositions effective in reducing inflammatory gene activity and / or cholesterol biosynthesis in a subject.

Description

Background of the invention [0001] The present invention relates to methods for identifying agents capable of effectively inhibiting inflammatory disease activity and / or cholesterol biosynthesis, as well as preparation and use of compositions containing the agents for the prevention and / or treatment of conditions associated with inflammatory disease activity and / or cholesterol biosynthesis Methods, such as atherosclerosis, inflammatory bowel disease, kidney disease, etc. The present invention relates to agents that are potent inhibitors of inflammatory gene activity and / or cholesterol biosynthesis. For example, the invention relates to inhibitors of nuclear receptors, such as short heterodimeric protein (SHP) and farnesoid X receptor (FXR). The present invention relates to compositions containing such inhibitors, including compositions effective for the prevention and / or treatment of diseases or conditions associated with inflammatory gene expression and / or cholesterol biosyn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04A61K31/07C07H21/04C07K14/47C07K14/70C12N15/11C12N15/85C12Q1/68G01N33/92
CPCG01N2500/10G01N33/92G01N2800/044A61P3/06A61P29/00A61K31/07C12Q1/6883C12Q1/6897
Inventor M·J·埃文斯D·C·哈尼斯
Owner WYETH HOLDINGS CORP
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