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Method for modulating FXR receptor activity

A technology of receptors and ligands, applied in the direction of organic active ingredients, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as elusive methods

Inactive Publication Date: 2002-09-11
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been known for some time that bile acids act in a negative feedback loop to limit their own production through this pathway, but the way this is done has remained elusive

Method used

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  • Method for modulating FXR receptor activity
  • Method for modulating FXR receptor activity
  • Method for modulating FXR receptor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Because it is known that FXR binds to its response element in the form of a heterodimer combined with RXR, and because the heterodimer can be activated by the ligand of RXR; therefore, a mutant RXRα protein (RXR m ; also referred to as D322P in the accompanying drawings), the mutant RXRα protein contains a point mutation in the ligand-binding domain of RXR (Asp 322 →Pro). FXR-RXR m The use of heterodimers allows the unambiguous identification of modulators of FXR activity among test compounds.

[0118] Therefore, a reporter plasmid containing 4 copies of the GAL4 response element UAS positioned upstream of the firefly luciferase gene was constructed G ; the GAL4 response element UAS G It is also under the control of the herpes simplex virus thymidine kinase (TK) promoter. This reporter plasmid was co-transfected into African green monkey CV-1 cells with an expression vector (pCMX, which contains the cytomegalovirus CMV promoter upstream of the cloning site), which e...

Embodiment 2

[0125] Because the transactivation activity of this FXR requires heterodimerization with RXR, although in ligand-dependent assays of FXR activity, RXR m Has a nonfunctional ligand binding domain; still do the following transactivation experiments to demonstrate RXR m retains its ability to potentiate FXR activity.

[0126] Recombinant full-length rat FXR and human RXR (or RXR) were cloned into the cloning site of plasmid pCMX using the transient transfection method generally described above. m ) were co-transfected into CV-1 cells. Additionally, the reporter plasmid was co-transfected with the expression plasmid described above.

[0127] By placing the cDNA coding sequence for firefly luciferase in frame immediately downstream of the herpes virus thymidine kinase promoter (located at nucleotide residues -105 to +51 of the thymidine kinase nucleotide sequence), to construct the luciferase reporter plasmid TK-Luc (described in Heyman et al., Cell 68:397 (1992), which is hereb...

Embodiment 3

[0135] Using the FXR-RXR used in Example 2 m A co-transfection method comparing the FXR agonist activity of AGN10 with the FXR activity of different bile acids; including deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), which are known to be naturally occurring FXR ligands ). See: eg, Wang et al., Molec. Cell 3:543-553 (May 1999), which is hereby incorporated by reference.

[0136] Encoded with full-length FXR and RXR m , and the luciferase reporter plasmid used in the last experiment above, to co-transfect CV-1 cells. The cells were then incubated for approximately 44 hours with one of the following reagents at a concentration of 100 nM; the following reagents were: LG268, AGN 10 (10 μM), 7-ketolithocholic acid, 3 , 7-diketolithocholic acid, ursodeoxycholic acid, a-murocholic acid, murocholic acid, dehydrocholic acid, taurocholic acid, cholic acid (CA), lithocholic acid (LCA), taurodeoxycholic acid taurodeoxycholic acid, deoxycholic acid (DCA), hydroxychenodeoxych...

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Abstract

Methods for modulating the activity of the mammalian FXR receptor. The methods include methods of treating a hyper- or hypocholesterolemic mammal comprising contacting the mammal with synthetic compounds having FXR receptor activity.

Description

[0001] This application claims priority under 35 USC 119(e) to Provisional Patent Application Serial No. 60 / 138,968, filed June 11, 1999, which is hereby incorporated by reference. field of invention [0002] The invention relates to the fields of human and veterinary medicine, physiology and biochemistry, in particular the regulation of lipid metabolism and catabolism and the synthesis and breakdown of cholesterol. Background of the invention [0003] In vivo, a vast array of specific metabolic, developmental, and catabolic processes appear to be directly or indirectly regulated by relatively small molecules such as steroids, retinoids, and thyroid hormones. The mechanism by which one such compound can cause regulation of a multitude of different cellular events has been the subject of much thought; only recently has it been discovered that each of these compounds shares the ability to bind to transcriptionally active protein receptors. These protein receptors in turn bind ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/551A61K31/553A61K31/554A61K31/695A61P1/16A61P3/06A61P9/10A61P35/00A61P43/00C07F7/08
CPCA61K31/551A61K31/553A61K31/554A61K31/695A61P1/16A61P35/00A61P3/06A61P43/00A61P9/10
Inventor B·M·福尔曼R·L·贝尔德R·A·钱德拉拉特纳
Owner ALLERGAN INC
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