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New DHA derivatives and their use as medicaments

A technology of drugs and compounds, applied to compounds of general formula: field

Inactive Publication Date: 2008-07-02
PRONOVA BIOPHARMA NORGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] However, none of these improved fatty acids have shown satisfactory pharmaceutical activity, and none have entered the pharmaceutical market

Method used

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  • New DHA derivatives and their use as medicaments
  • New DHA derivatives and their use as medicaments
  • New DHA derivatives and their use as medicaments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0393] Example 1: Analysis of Intracellular Free Fatty Acids (Non-Esterified Fatty Acids) in Hepatocytes (Group 1 in Figure 2)

[0394] background

[0395] In the first set of experiments (Figure 2), free unesterified fatty acids were analyzed in liver tissue from animals dosed with PRB-1, 2, 5 and 7. These animals were transferred from the fifth set of experiments (Pharmacokinetic Effects of DHA Derivatives in Animal Models of Metabolic Syndrome). These animals have been given DHA (diet with 15% fat content) or DHA-derivatives (1.5% fat content in their diet) for 8 weeks and are assumed to be in a stable state with intracellular stable levels of DHA and DHA-derivatives. state. Since the rate of metabolism in the liver is very fast, liver tissue was selected.

[0396] method

[0397] The liver samples were homogenized in cold PBS buffer, immediately extracted with chloroform:methanol (2:1) containing 0.2 mM butylated hydroxytoluene (BHT), using cis-10- Heptadecenoic acid ...

Embodiment 2

[0404] Example 2: Computer Aided Affinity Test (Group 2 in Figure 2)

[0405] background

[0406] Nuclear receptors have been sequenced and amino acid sequences are known for PPARs and other related receptors used in the genetic control of glucose and fat. X-ray crystal structures and NMR spectra of PPARs are available, so computational affinity tests of fatty acid binding to receptors can be used to assess binding kinetics. Binding geometry, often referred to as binding mode or pose, includes both the position of the ligand relative to the receptor and the conformational state of the ligand and receptor, thus enabling the analysis of efficient ligand docking.

[0407] The affinity of the ligand for the receptor is defined by two distinct parameters: the docking of the ligand (DHA derivative) to the binding site of the receptor and the specific amino acid of the receptor and the carbonyl group or side chain in the fatty acid front. Electrostatic bonding (Krumrine).

[0408]...

Embodiment 3

[0423] Example 3: Affinity testing in transfected cells (Group 3 in Figure 2)

[0424] background

[0425] The release of luciferase correlates with the transcription of the gene. Binding of ligands to nuclear receptors such as PPARγ induces the transcription of the respective genes, thus releasing luciferase. This technique thus provides a means to measure ligand affinity for receptors and the activation of responsive genes.

[0426] method

[0427] Transient transfection of COS-1 cells in 6-well plates was performed as described by Graham and van der Eb (Graham). For full-length PPAR transfection studies, each well received 5 μg of the reporter construct, 2.5 μg of pSV-β-galactosidase as an internal control, 0.4 μg of pSG5-PPARγ2. Cells were harvested after 72 hours and luciferase activity was measured according to the protocol (Promega). Luciferase activity was normalized to β-galactosidase activity. Using 16 μl of lipofectamine Plus reagent, 4 μl of lipofectamine (Li...

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Abstract

Compounds of formula (I); wherein - R1 and R2 are the same or different and may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; and - X represents a carboxylic acid group, a carboxylate group, or a carboxamide group; or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof, with the provisos that the compound of formula (I) is not (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester, are disclosed. A fatty acid composition and a pharmaceutical composition comprising such compounds are also disclosed. The use of such compounds as medicaments, in particular for the treatment of diabetes type 2, is also disclosed.

Description

technical field [0001] The present invention relates to compounds of general formula (I): [0002] [0003] As well as their use as medicines, especially in the treatment of type 2 diabetes mellitus and its predose, it also relates to pharmaceutical compositions containing compounds of formula (I), and fatty acid compositions containing compounds of formula (I). Background of the invention [0004] The worldwide increase in the incidence of type 2 diabetes poses enormous public health and medical challenges to the implementation of successful prevention and treatment strategies. The comorbidities of overweight and obesity, which are closely related to type 2 diabetes, hamper diabetes management and increase the likelihood of hypertension, dyslipidemia, and atherosclerosis-related diseases. [0005] The pathophysiological condition that precedes the development of type 2 diabetes is associated with a reduced effect of insulin on peripheral tissues, termed insulin resistan...

Claims

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Application Information

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IPC IPC(8): C11C3/00A61K31/202A61K31/232A61K31/421A61P3/04A61P3/10A61P9/10C07C57/03C07C69/587C07D263/24
Inventor 莫滕·布赖恩安妮·K·霍尔梅德简·科佩基
Owner PRONOVA BIOPHARMA NORGE
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