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Inhibitors of anorexic lipid hydrolysis for the treatment of eating disorders

An appetite suppression and application technology, applied in the field of anorexia lipid hydrolysis inhibitors for the treatment of eating disorders, can solve the problems of reducing bioavailability and therapeutic effect and the like

Inactive Publication Date: 2008-08-20
UNIVERSITY OF COPENHAGEN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although oral administration of these appetite suppressant acylamides has been proposed for the treatment of obesity (WO02 / 080860), their rapid degradation in the intestinal and gastric system (7) reduces their bioavailability and therapeutic efficacy

Method used

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  • Inhibitors of anorexic lipid hydrolysis for the treatment of eating disorders
  • Inhibitors of anorexic lipid hydrolysis for the treatment of eating disorders
  • Inhibitors of anorexic lipid hydrolysis for the treatment of eating disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Example 1. Effect of D-erythro-MAPP, D-threo-NMAPPD and URB597 on A) OEA and anandamide hydrolysis and B) ceramide hydrolysis of intestinal proteins from (URB597-treated) rats .

[0150] The goal of this in vitro study (Examples 1-2) was to demonstrate that partial OEA hydrolysis in intestinal tissue is due to an enzyme other than FAAH, which is characterized as an acylethanolamide / acylamide hydrolase, which acts on anandamide (AEA) is about 5 times more selective than OEA (21).

[0151] 1A: OEA hydrolysis was determined according to an experiment modified on the basis of Fegley et al. (14), using 50 μg of intestinal protein from male Sprague-Dawley rats (about 200 g) of URB597 (Cayman Chemical, Ann Arbor, MI, USA) treated (0.3 mg / kg i.p.1h before anesthesia) and untreated [4ml / kg vehicle (saline / Tween80 / polyethylene glycol; 90:5:5) i.p.1h before anesthesia], with 28μM [ 1- 3 H-Ethanolamine] OEA (from American Radiolabeled Chemicals, Inc., St.Louis, MO, USA, diluted ...

Embodiment 2

[0154] Example 2. pH dependence of A) OEA hydrolysis, B) ceramide hydrolysis, and C) arachidonic acid ethanolamide hydrolysis by (URB597-treated) rat intestinal proteins.

[0155] 2A: pH-dependence of OEA hydrolysis in the absence of D-erythro-MAPP Experiments were carried out using conditions similar to those described in Example 1A, with 50 μg of intestinal protein from Sprague Dawley rats (about 200 g), which URB597 treated (0.3mg / kg i.p.1h before anesthesia) and untreated [4ml / kg vehicle (saline / Tween 80 / polyethylene glycol; 90:5:5) i.p.1h before anesthesia], with 28μM [1- 3 H-ethanolamine] OEA (10 dpm / pmol) was incubated at 37°C for 0, 10, 20 and 30 min in a total volume of 200 μl of different buffers containing 0.9 mM EDTA, 1.5 mg / ml fatty acid-free bovine serum albumin . Alternatively, use 25 μg protein from rat intestinal (jejunum) homogenate in a total volume of 100 μl, and 50 μM 3 H-oleoylethanolamide (OEA; 25.000 dpm), with or without 10 μM of URB597 (200 μM in 5...

Embodiment 3

[0160] Example 3. Inhibition of food intake in mice / rats following administration of MAPP / NMAPPD

[0161] In order to evaluate the effect of ceramidase inhibitors on food intake - possibly by prolonging the effect of endogenously produced OEA, the following in vivo experiments were designed. Furthermore, co-administration of submaximal doses of OEA with ceramidase inhibitors is planned to further demonstrate the possible mode of action of the compounds of the present invention.

[0162] 3A: Inhibition of food intake in rats following administration of an inhibitor of ceramidase. Thirty male Sprague Dawley rats (6 weeks old, approximately 190 g, Charles River, Germany) were used following the acclimatization protocol described above. Rats were randomized into weight-matched n=6 groups and then fasted for 24 h with food removed just before the start of the dark period. The next day they received an acute dose of 0.05; 0.2; 0.5; 2; or 5 mg / kg of D-erythro-MAPP or vehicle (salin...

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Abstract

Compounds, pharmaceuticals, cosmetic or dietary supplements for the treatment of overweight, obesity and / or type II diabetes in a mammal (e.g. human) comprising a compound with formula I or formula II for example ceramidase-inhibitor, such as (1S,2R)-D-erythro-2-(N-myristoylamino)-1- phenyl-1-propanol, alone or in combination with an anorexic lipid (or other appetite-inhibiting acylamides or oleoyl-estrone), and methods of treatment comprising administration of said compounds, pharmaceuticals, cosmetic or a dietary supplements. The compounds, pharmaceuticals, cosmetic or dietary supplements and methods of the invention may further be used in modifying the feeding behaviour, suppression of hunger, enhancement of satiety, reduction of energy intake, reduction of fat tissue mass / lean mass ratio in a mammal (e.g. human).

Description

Background of the invention [0001] Obesity is associated with numerous health risks, ranging from non-fatal and debilitating conditions such as osteoarthritis to life-threatening chronic diseases such as coronary heart disease, type II diabetes and certain types of cancer. The physiological consequences of obesity can range from diminished self-esteem to clinical depression (1). The prevalence of obesity is increasing in an epidemic fashion in both developed and underdeveloped countries (2). Because dietary therapy is often less successful in the long term, there is an increasing need for drug therapy, and a number of different drug targets have been proposed (1-3). Reduced nutrient absorption, appetite suppression, and increased thermogenesis are being considered, but all have drawbacks. Reduced nutrient absorption, for example by inducing inappropriate fat absorption, may affect gastrointestinal function and cause gastrointestinal distress. Appetite suppression is general...

Claims

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Application Information

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IPC IPC(8): A61K31/165A61K31/047A61P3/04
Inventor H·S·汉森G·彼得森A·阿特曼P·J·拉森
Owner UNIVERSITY OF COPENHAGEN
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