Method for assaying compounds or agents for ability to decrease the activity of microsomal prostaglandin E synthase or hematopoietic prostaglandin D synthase

A prostaglandin and compound technology, applied in the screening of compounds, chemical treatment to inactivate enzymes, biochemical equipment and methods, etc., can solve the problems of undetectable fluorescence emission and achieve high-throughput effects

Inactive Publication Date: 2005-09-28
AVENTIS PHARMA INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As a result, no fluoresc...

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  • Method for assaying compounds or agents for ability to decrease the activity of microsomal prostaglandin E synthase or hematopoietic prostaglandin D synthase
  • Method for assaying compounds or agents for ability to decrease the activity of microsomal prostaglandin E synthase or hematopoietic prostaglandin D synthase
  • Method for assaying compounds or agents for ability to decrease the activity of microsomal prostaglandin E synthase or hematopoietic prostaglandin D synthase

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[0076]The preparation of combinatorial compound libraries is well known to those of ordinary skill in the art. Such combinatorial compound libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Pat. -88). The synthesis of peptides is by no means the only method foreseen and contemplated for use in the present invention. Other chemistries that generate chemical multiplex libraries can also be used. Such chemical substances include, but are not limited to: peptoids (PCT publication WO 91 / 19735, December 26, 1991), encoded peptides (PCT publication WO 93 / 20242, October 14, 1993), Japan), random bio-oligomers (PCT Publication WO 92 / 00091, January 9, 1992), benzodiazepines (U.S. Patent No. 5,288,514), diversomers such as hydantoins Classes, benzodiazepines and dipeptides, etc. (Hobbs et al., (1993) Proc.Nat.Acad.Sci.USA 90: 69096913), vinylogous polypeptides (vinylogouspolypeptides) (Hagihara et al. (1992) J.Amer.Chem. Soc.114:6568), non-peptidic peptidom...

Embodiment I

[0083] Fluorescence Polarization Assay of Inducible Microsomal Prostaglandin E Synthase (mPGES)

[0084] Prostaglandin E 2 (PGE 2 ) is a major mediator involved in inflammation and pain. Microsomal prostaglandin E synthase (mPGES) catalyzes PGH in the presence of glutathione 2 to PGE 2 transformation. It induces the expression of mPGES in many inflammatory diseases. Accordingly, compounds that reduce or inhibit the activity of mPGES would be useful agents for the treatment of inflammation, pain, fever, or combinations of these conditions, to name only a few diseases or disorders.

[0085] Inducible microsomal PGE has been developed 2 synthase to measure PGH 2 to PGE 2 Transformation test method. The test method is designed according to the principle of fluorescence polarization. PGH 2 , glutathione, and the compound or reagent being evaluated. After a short incubation (at least 30 seconds), add FeCl-containing 2 and a stop solution of citric acid to quench any r...

Embodiment II

[0107] Fluorescence polarization analysis of hematopoietic prostaglandin D synthase (hPGDS)

[0108] Antigenic stimulation will increase PGD in airway allergic diseases 2 generation. PGH is produced by hematopoietic prostaglandin D synthase (hPGDS) 2 Convert to PGD 2 PGD 2 , binds to both the D-type prostaglandin receptor (DP) and the chemokine receptor for Th2 cells (CRTH2), and increases bronchoconstriction, vasodilation, and dilatation of the nasal mucosa. The resulting bronchial hyperactivity, nasal obstruction, and infiltration of eosinophils and Th2 cells lead to allergic reactions. Therefore, compounds or agents that reduce or inhibit the activity of hPGDS can readily be used as therapeutic agents.

[0109] Fluorescence polarization (FP) assays (Figures 3 and 4), which measure hPGDS activity, were also investigated. The assay is designed based on the principle of fluorescence polarization. Combine hPGDS with PGH 2 , glutathione, and the compound or reagent bei...

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Abstract

Provided herein is a novel and useful method for evaluating the ability of compounds or agents to decrease the activity of microsomal prostaglandin E synthase or hematopoietic prostaglandin D synthase to produce their respective prostaglandin products.

Description

field of invention [0001] The present invention relates to a novel and useful method for testing the ability of compounds or agents to reduce the activity of prostaglandin synthase. More specifically, the present invention relates to a method of testing the ability of a compound or agent to decrease microsomal prostaglandin E synthase (mPGES) activity or hematopoietic prostaglandin D synthase (hPGDS) activity. Background of the invention [0002] Prostaglandins are a class of eicosanoids that play an important role in pain, fever, and inflammatory processes. They are synthesized in vivo from arachidonic acid and have a five-membered carbon ring that forms part of the arachidonic acid carbon chain. Prostaglandins are not hormones and act only locally near the site where they are synthesized. [0003] PGE 2 and PGD 2 Both prostaglandins play a particularly important role in fever, pain and inflammation. In particular, PGD produced by mast cells in response to antigenic st...

Claims

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Application Information

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IPC IPC(8): A61KC12N9/99C12N15/09C12Q1/00C12Q1/533G01N33/53
CPCG01N2500/04C12Q1/533A61P29/00A61P43/00G01N33/53C12N9/99C12N15/09
Inventor 李竹吟熊俊杰J·S·萨伯尔Y·H·马
Owner AVENTIS PHARMA INC
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