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Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions

a bile acid recycling inhibitor and satiogen technology, applied in the direction of drug compositions, amide active ingredients, metabolic disorders, etc., can solve the problems of diabetes, nec remains a major cause of morbidity and mortality in premature infants, overeating and obesity, etc., to reduce the bile acid salt recycling or inhibit the effect of bile acid salt recycling, reducing intraenterocyte bile acids, and reducing necrosis and/or damage to ileal architectur

Inactive Publication Date: 2011-12-01
SATIOGEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004]Provided herein, in certain embodiments, are therapeutic methods using compounds that inhibit the Apical Sodium-dependent Bile Transporter (ASBT) or any recuperative bile salt transporter. In certain instances, use of the compounds provided herein reduces or inhibits recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided herein reduce intraenterocyte bile acids or reduce necrosis and / or damage to ileal architecture. In some embodiments, the bile transport inhibitors are non-systemic compounds. In other embodiments, the bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein enhance L-cell secretion of enteroendocrine peptides.

Problems solved by technology

Overeating and obesity, which frequently leads to diabetes, have become a problem in the general population.
Mortality rates of NEC are between 10 to 50%, and thus NEC remains a major cause of morbidity and mortality in premature infants.

Method used

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  • Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions
  • Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions
  • Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions

Examples

Experimental program
Comparison scheme
Effect test

example 1

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

[0646]

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

[0647]

[0648]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

[0649]

[0650]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

[0651]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.

[0652]The compounds i...

example 2

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

[0653]Baby hamster kidney (1311K) 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.

[0654]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-1

[0655]Human NCI-H1-716 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-1. Peptides in the medium are collected by reverse phase adsorption and the extracts are stored until assay. The presence of GLP-1 is assayed using an antiserum directed against the carboxyl terminus of GLP-1 amide (total immunoreactive GLP-1; Affinity Research Products, Nottingham, UK). The detection of increased levels of GLP-1 in a well containing a test compound identifies the test compound as a compound that can enhance GLP-1 secretions from L-cells.

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Abstract

Provided herein are methods of utilizing bile acid transport inhibitors and / or enteroendocrine peptide enhancing agents for the treatment of obesity, diabetes, and inflammatory gastrointestinal conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 61 / 348,666, filed May 26, 2010, and U.S. Provisional Application No. 61 / 348,669, filed May 26, 2010, each of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Diabetes and obesity affect numerous humans throughout the world, and are associated with or induces other diseases or conditions. In particular, diabetes and obesity are serious risk factors for diseases and conditions such as hypertension, gallbladder disease, cancer, polycystic ovary disease and arteriosclerosis and can contribute to elevated levels of cholesterol in the blood. Overeating and obesity, which frequently leads to diabetes, have become a problem in the general population. Consequently there is interest in reducing food intake, losing weight, and reducing elevated blood glucose.[0003]Inflammatory gastrointestinal conditions affect mi...

Claims

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Application Information

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IPC IPC(8): A61K31/554A61K31/38A61K31/4453A61K31/454A61K31/40A61K31/495A61K31/16A61K31/5377A61K31/155A61K31/575A61P1/00A61P1/04A61K31/56A61K31/4418A61K31/4995
CPCA61K9/0031C07D487/08A61K9/286A61K31/155A61K31/16A61K31/18A61K31/19A61K31/191A61K31/216A61K31/38A61K31/40A61K31/42A61K31/452A61K31/454A61K31/495A61K31/4985A61K31/4995A61K31/513A61K31/5377A61K31/55A61K31/554A61K31/575A61K31/655A61K31/7042A61K45/06A61K9/02C07D295/13C07D401/12A61K31/496C07C279/14A61K2300/00A61P1/00A61P1/04A61P29/00A61P3/04A61P3/10
Inventor GEDULIN, BRONISLAVAYOUNG, ANDREW A.GREENE, HOWARD E.
Owner SATIOGEN PHARMA
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