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Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease

a bile acid recycling inhibitor and liver disease technology, applied in the direction of esterified saccharide compounds, drug compositions, cyclic peptide ingredients, etc., can solve the problems of limited active treatment and prevention, reduce the recurrence of hypercholemia, and reduce the severity of symptoms

Inactive Publication Date: 2014-10-30
LUMENA PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes methods and compounds that can inhibit the ASBT or any recuperative bile salt transporter. Using these compounds can reduce recycling of bile acid salts in the gastrointestinal tract and prevent damage to the intestine and liver. The compounds can also enhance the secretion of enteroendocrine peptides by intestinal L-cells. The ASBTI can be delivered orally and can be formulated to provide prolonged or sustained delivery of the drug to the gastrointestinal tract. The formulation can use enteric coatings to control the release of the drug molecule.

Problems solved by technology

Active treatment and prevention is limited.

Method used

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  • Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease
  • Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease
  • Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease

Examples

Experimental program
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Effect test

example 1

Synthesis of 1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octanyl)pentyl)imidodicarbonimidic diamide, iodide salt

[0654]

Step 1: Synthesis of 5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodide salt

[0655]

[0656]1,4-diazabicyclo[2.2.2]octane is suspended in THF. Diiodopentane is added dropwise and the mixture is refluxed overnight. The reaction mixture is filtered.

Step 2: Synthesis of N-phenethyl-5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodide salt

[0657]

[0658]5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodide salt is suspended in acetonitrile. Phenethylamine is added dropwise and the mixture is refluxed overnight. The reaction mixture is filtered.

Step 3: Synthesis of 1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octanyl)pentyl)imidodicarbonimidic diamide, iodide salt

[0659]N-phenethyl-5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodide salt is heated with dicyanodiamide in n-butanol for 4 h. The reaction mixture is concentrated under reduced pressure.

[0660]The compounds i...

example 2

In Vitro Assay for Inhibition of ASBT-Mediated Bile Acid Uptake

[0661]Baby hamster kidney (BHK) cells are transfected with cDNA of human ASBT. The cells are seeded in 96-well tissue culture plates at 60,000 cells / well. Assays are run within 24 hours of seeding.

[0662]On the day of the assay the cell monolayer is washed with 100 mL of assay buffer. The test compound is added to each well along with 6 mM [14C] taurocholate in assay buffer (final concentration of 3 mM [14C] taurocholate in each well). The cell cultures are incubated for 2 h at 37° C. The wells are washed with PBS. Scintillation counting fluid is added to each well, the cells are shaken for 30 minutes prior to measuring amount of radioactivity in each well. A test compound that has significant ASBT inhibitory activity provides an assay wherein low levels of radioactivity are observed in the cells.

example 3

In Vitro Assay for Secretion of GLP-2

[0663]Human NCI-H716 cells are used as a model for L-cells. Two days before each assay experiment, cells are seeded in 12-well culture plates coated with Matrigel® to induce cell adhesion. On the day of the assay, cells are washed with buffer. The cells are incubated for 2 hours with medium alone, or with test compound. The extracellular medium is assayed for the presence of GLP-2. Peptides in the medium are collected by reverse phase adsorption and the extracts are stored until assay. The presence of GLP-2 is assayed using ELISA. The detection of increased levels of GLP-2 in a well containing a test compound identifies the test compound as a compound that can enhance GLP-2 secretions from L-cells.

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Abstract

Provided herein are methods of treating or ameliorating hypercholemia or a cholestatic liver disease 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. Also provided are methods for treating or ameliorating a liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising administering to an individual in need thereof a therapeutically effective amount of ASBTI or a pharmaceutically acceptable salt thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 553,094, filed Oct. 28, 2011, U.S. Provisional Application No. 61 / 607,487, filed Mar. 6, 2012, which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Hypercholemia and cholestatic liver diseases are liver diseases associated with impaired bile secretion (i.e., cholestasis), associated with and often secondary to the intracellular accumulation of bile acids / salts in the hepatocyte. Hypercholemia is characterized by increased serum concentration of bile acid or bile salt. Cholestasis can be categorized clinicopathologically into two principal categories of obstructive, often extrahepatic, cholestasis, and nonobstructive, or intrahepatic, cholestasis. Nonobstructive intrahepatic cholestasis can further be classified into two principal subgroups of primary intrahepatic cholestasis that result from constitutively defective bile sec...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H13/12C07D337/08C07D281/10C07D211/06A61K31/4453C07D401/12A61K31/454C07D295/13A61K31/495C07C279/12C07D207/04A61K31/5377A61K31/4995A61K31/38A61K31/7028A61K31/554C07D285/36A61K45/06C07D487/08
CPCC07H13/12A61K45/06C07D337/08C07D281/10C07D211/06A61K31/4453C07D401/12A61K31/454C07D295/13A61K31/495C07C279/12C07D207/04A61K31/5377A61K31/4995A61K31/38A61K31/7028A61K31/554C07D285/36C07D487/08A61P1/16A61K31/704C07H15/18A61K31/155A61K31/40A61K31/4436A61K31/7042C07D211/08C07D413/12A61P17/04Y02A50/30A61K2300/00C07C257/10C07H15/26A61P43/00
Inventor GEDULIN, BRONISLAVAGREY, MICHAELO'DONNELL, NIALL
Owner LUMENA PHARMA LLC
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