Methods of using substituted isoxazolo pyridinones as dissociated glucocorticoids

a technology of isoxazolo pyridinone and dissociated glucocorticoids, which is applied in the field of glucocorticoid receptors, can solve the problems of side effects, diabetes, osteoporosis, and significant transactivation activity, and achieves significant transactivation activity

Active Publication Date: 2010-07-15
VAN ANDEL RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, corticoid-like drugs can result in side effects because of the unwanted transactivation activity of GR.
As such, long term use of corticoid-like drugs can lead to diabetes, osteoporosis, skin atrophy, and growth retardation.
Thus, an important issue for corticoid-like anti-inflammatory drug discovery is to identify a GR ligand which can retain or increase GR transrepression activity, but with only minimal remaining GR transactivation activity.
However, all of the known attempts to identify a dissociated GR ligand have resulted in a GR ligand that either (a) retains only a very small part of its transrepression activity, or (b) has significant transactivation activity, e.g., undesirable side effects.
As such, none of these known compounds has been used in a clinical setting to date.

Method used

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  • Methods of using substituted isoxazolo pyridinones as dissociated glucocorticoids
  • Methods of using substituted isoxazolo pyridinones as dissociated glucocorticoids
  • Methods of using substituted isoxazolo pyridinones as dissociated glucocorticoids

Examples

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Effect test

example 1

GR Transactivation on MMTV in∘AD293 Cells Transfected with 0.5 ng GR

[0090]AD293 cells were transfected with 0.5 ng GR, 100 ng pHHLuc reporter together with 5 ng Renilla control plasmids, then induced by EtOH (vehicle control), Dexamethasone (10 nM), Compound #53 (5 μM), AL438 (1 μM) and DMSO (vehicle control). Dual-Luciferase values were measured by Promega standard manual, Compound #53's transactivation activity on MMTV in AD293 cells is shown in FIG. 5.

example 2

GR Transrepression of AP1 in AD293 Cells Transfected with 10 ng GR

[0091]AD293 cells were transfected with 10 ng GR, 100 ng AP1-Luc reporter together with 5 ng Renilla control plasmids, then induced by EtOH (vehicle control), Dexamethasone (10 nM), Compound #53 (5 μM), AL438 (1 μM). Dual-Luciferase values were measured by Promega standard manual. Compound #53's GR transrepression activity on AP1 in AD293 cells is shown in FIG. 6.

example 3

GR Transpression of AP 1 in AD293 Cells Transfected with 50 ng GR

[0092]AD293 cells were transfected with 50 ng GR, 100 ng AP1-Luc reporter together with 5 ng Renilla control plasmids, then induced by PMA+EtOH (vehicle control), PMA+Dexamethasone (10 nM), PMA+Compound #53 (5 μM). Dual-Luciferase values were measured by Promega standard manual. Compound #53's GR transrepression activity on AP1 in AD293 cells is shown in FIG. 7.

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Abstract

A method for treating a subject having an inflammatory or auto-immune disease with a substituted isoxazolo pyridinone. Also, a method for administering a substituted isoxazolo pyridinone to a cell to retain or increase glucocorticoid receptor transrepression activity with only minimal glucocorticoid receptor transactivation activity.

Description

[0001]This application claims benefit of provisional application Ser. No. 61 / 144,326, filed Jan. 13, 2009, entitled Methods of Using Substituted Isoxazolo Pyridinones as Dissociated Glucocorticoids, the entire contents of which are incorporated herein in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was in part made with United States government support awarded by the following agency: National Institute of Health NIH grant number DK 071662. The United States has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]The glucocorticoid receptor (GR) is a steroid hormone receptor which belongs to the nuclear receptor superfamily (nuclear receptor subfamily 3, group C, member 1). GR is encoded by gene NR3C1 on chromosome 5 (5q31). GR plays an important role in many physiologic processes, such as regulating glucose and lipid metabolism, bone development, and maintaining body salt balance.[0004]GR exerts its physiologic rol...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4439A61P19/02A61P11/06A61P35/02A61P29/00A61P3/00A61P9/10A61P25/00A61K31/496
CPCA61K31/437A61K31/496A61K31/444A61K31/4439A61P3/00A61P9/10A61P11/06A61P19/02A61P25/00A61P29/00A61P35/02A61P37/00
Inventor XU, HUAQIANG ERICXU, YONGHE, YUANZHENG
Owner VAN ANDEL RES INST
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