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Bile acid recycling inhibitors for treatment of barrett's esophagus and gastroesophageal reflux disease

A technique for gastroesophageal reflux and bile acids, applied to treat or improve Barrett's esophagus, pharmaceutical composition for treating GERD, pharmaceutical composition for treating or improving Barrett's esophagus and GERD, treating Barrett's esophagus and GERD A pharmaceutical composition, a pharmaceutical composition for the treatment of Barrett's esophagus, for the treatment or amelioration of the GERD field, capable of addressing the increased risk etc.

Inactive Publication Date: 2016-01-06
LUMENA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients with Barrett's esophagus are at increased risk of developing esophageal adenocarcinoma

Method used

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  • Bile acid recycling inhibitors for treatment of barrett's esophagus and gastroesophageal reflux disease
  • Bile acid recycling inhibitors for treatment of barrett's esophagus and gastroesophageal reflux disease
  • Bile acid recycling inhibitors for treatment of barrett's esophagus and gastroesophageal reflux disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0766] Example 1: Synthesis of 1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octyl)pentyl)iminodiiminoformamide iodide salt

[0767]

[0768] step 1: Synthesis of 5-(1,4-diazabicyclo[2.2.2]octyl)-1-iodopentane iodide salt

[0769]

[0770] 1,4-Diazabicyclo[2.2.2]octane was suspended in THF. Diiodopentane was added dropwise, and the mixture was refluxed overnight. The reaction mixture was filtered.

[0771] Step 2: Synthesis of N-phenethyl-5-(1,4-diazabicyclo[2.2.2]octyl)-1-iodopentane iodide salt.

[0772]

[0773] 5-(1,4-Diazabicyclo[2.2.2]octyl)-1-iodopentane iodide salt was suspended in acetonitrile. Phenylethylamine was added dropwise, and the mixture was refluxed overnight. The reaction mixture was filtered.

[0774] Step 3: Synthesis of 1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octyl)pentyl)iminodiiminoformamide iodide salt.

[0775] N-phenethyl-5-(1,4-diazabicyclo[2.2.2]octyl)-1-iodopentane iodide was heated with dicyanodiamide in n-butanol for 4 h . The ...

Embodiment 2

[0779] Example 2: In Vitro Assay for ASBT-Mediated Inhibition of Bile Acid Uptake

[0780]Baby hamster kidney (BHK) cells were transfected with cDNA of human ASBT. Cells were seeded in 96-well tissue culture plates at 60,000 cells / well. Assays were performed within 24 hours of inoculation.

[0781] On the day of the assay, wash the cell monolayer with 100 mL of assay buffer. The test compound was mixed with 6mM [ 14 C] Taurocholate was added together to each well (final concentration in each well was 3 mM [ 14 C] Taurocholate). Cell cultures were incubated at 37°C for 2h. Wells were washed with PBS. Scintillation fluid was added to each well and the cells were shaken for 30 minutes before measuring the amount of radioactivity in each well. Test compounds with significant ASBT inhibitory activity provide an assay in which low levels of radioactivity are observed in cells.

Embodiment 3

[0782] Example 3: In vitro assay for secretion of GLP-2

[0783] Human NCI-H716 cells were used as a model for L-cells. Two days before each assay experiment, cells were plated in Coated 12-well culture plates to induce cell adhesion. On the day of the assay, cells were washed with buffer. Cells were incubated with medium alone or with test compounds for 2 hours. Extracellular media were analyzed for the presence of GLP-2. Peptides in the medium were collected by reverse phase adsorption and the extracts were stored until assayed. ELISA was used to analyze the presence of GLP-2. Detection of increased GLP-2 levels in wells containing the test compound identifies the test compound as a compound that enhances GLP-2 secretion from L-cells.

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Abstract

Provided herein are methods of treating or ameliorating Barrett's esophagus by administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Provided herein are methods of treating or ameliorating gastroesophageal reflux disease (GERD) by administering to an individual in need thereof a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating symptoms or complications associated with Barrett's esophagus or GERD comprising administering to an individual in need thereof a therapeutically effective amount of ASBTI or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Patent Application Serial No. 61 / 798,876, filed March 15, 2013, which is hereby incorporated by reference in its entirety. Background of the invention [0003] Barrett's esophagus is a disorder in which the lining of the esophagus is damaged by gastroesophageal reflux and changes to that of the stomach or intestine (ie, intestinal metaplasia). Barrett's esophagus is a serious complication of gastroesophageal reflux disease (GERD), which is a chronic symptom of mucosal injury caused by gastric acid reflux. Barrett's esophagus and GERD share associated symptoms. However, patients with Barrett's esophagus have an increased risk of developing esophageal adenocarcinoma. Aggressive treatment and prevention are limited. Summary of the invention [0004] Provided herein are therapeutic compositions and methods for treating or ameliorating Barrett's esophagus and gastroes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/38A61P1/00
CPCA61K31/38A61K31/554C07D313/08C07D249/14C07D207/09C07D487/08C07D295/13C07D207/16A61K31/4995A61K45/06A61P1/00A61P1/04A61P43/00
Inventor 布罗尼斯拉娃·格杜林迈克尔·格雷尼尔·奥唐奈布拉德利·T·凯勒
Owner LUMENA PHARMA INC
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