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New drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases

Inactive Publication Date: 2011-12-01
LUDWIG MAXIMILIANS UNIV MUNCHEN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

wherein Hal is Cl or Br, preferably Hal is Br.

Problems solved by technology

A large number of neurological and neurodegenerative diseases are known, many of which are presently not curable.
However, none of these compounds have so far been used successfully for disease treatment or as lead compounds for developing compounds with increased therapeutic potency and pharmacological properties.
Few in vitro assays suitable for high-throughput screening of large compound libraries for potential anti-prion drugs have been established so far.
However, these approaches allowed the screening of libraries limited to 2500 and 2000 compounds, respectively, and turned out to be time-consuming.
However, the mechanism of action of this method has not been elucidated so far.
All three methods face the same problem, namely passage of the molecules through the blood-brain barrier.
Due to this drawback, these approaches are only suitable for post exposition prophylaxis in peripheral organs but not for therapy of the disease in the central nervous system.
So far, no therapeutic strategies are available for the inhibition of aggregation of α-synuclein.

Method used

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  • New drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases
  • New drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases
  • New drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification of a Novel Class of Compounds for Inhibiting Protein Aggregation

[0196]Two subsets of the commercial compound library DIVERSet (ChemBridge Corp., San Diego, Calif., USA), each containing 10.000 compounds, and called DIVERSet 1 and 2 by us, have been screened for inhibitors of prion propagation using the 2D-SIFT anti-prion assay (Bertsch et al. 2005) and a cell culture model of prion disease. In both assays primary hits were obtained by testing compounds at a single concentration and subsequently verified in dilution series. Additionally, cell culture hits were tested using another cell line.

2DSIFT Screening

[0197]To test the inhibitory effect of drugs on the association between PrPC and PrPSc in a high-throughput and high-content screening assay, we applied the “Scanning for Intensely Fluorescent Targets” (SIFT-) technique, which utilises an inverted dual color confocal microscope setup with single photon detectors for two colors of fluorescent light. Samples are prepar...

example 2

Synthesis of New Drugs for Inhibiting Aggregation Under Medicinal-Chemical Aspects

[0206]Based on the discovery of the new lead structure as described above, a number of further substances were synthesised by selective substitution of different substituents, as outlined below.

(E)-1-(3,4-Dimethoxyphenyl)-3-(3-fluorophenyl)-2-propene-1-one (1) [Nam et al., 2004]

[0207]A solution of 3,4-dimethoxyacetophenone (1.8 g, 10 mmol), 3-fluorobenzadehyde (1.24 g, 10 mmol), NaOH (50 mg, 1.25 mmol) and Ba(OH)2.8H2O (100 mg, 0.32 mmol) in methanol (10 ml) was stirred at room temperature for 24 h. The reaction was cooled to +4° C., resulting precipitate was collected by filtration, recrystallized from methanol and dried to provide 1 (1.65 g, 58%) as a yellow powder.

2,3-Dibromo-1-(3,4-dimethoxyphenyl)-3-(3-fluorophenyl)-propan-1-one (2) [Harris et al., 1977]

[0208]To a solution of 1 (715 mg, 2.5 mmol) in chloroform (11 ml) was added dropwise a solution of bromine (400 mg, 2.5 mmol) in chloroform (4 ml)...

example 3

Material and Methods Used

Compound Libraries

[0246]The libraries screened contain 10.000 compounds each and are called DIVERSet1 and DIVERSet2 by us, because they cover only a part of the larger DIVERSet library (ChemBridge Corp., San Diego, Calif.). DIVERSet is a collection of rationally selected, diverse, drug-like small molecules. The compounds were supplied in dimethyl sulfoxide (DMSO) solution and on 96-well microtiter plates. A database containing molecular structures and some physico-chemical data for each of the compounds is available at www.chembridge.com.

Production of Recombinant Mouse PrP 23-231

[0247]Recombinant PrP 23-231 was produced and purified essentially as described by Liemann et al. (1998), except that for bacterial expression BL21DE3 RIL E. coli cells (Novagen) were transformed with plasmid pET17b-MmPrP23-231WT31 for mouse PrP23-231. Also, the bacteria were grown to an optical density of 0.5 before protein production was induced by addition of 1 mM IPTG and cells h...

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Abstract

The present invention relates to a compound represented by formula (E). The present invention also relates to a compound represented by the formula (E) for use in the treatment or prevention of diseases linked to protein aggregation and / or neurodegenerative diseases. Moreover, the present invention relates to pharmaceutical and diagnostic compositions comprising the compound of the invention as well as to a kit. Furthermore, the present invention relates to a method of imaging deposits of aggregated protein. A kit for preparing a detectably labelled compound of the present invention is also disclosed. Formula (E) wherein X, Y and L are independently nondirectionally selected from —C(R1)(R2)—, —C(R3)═, —N(R4)—, —N═, —N+(R5)═, —O— and —S—; M and Z are independently nondirectionally selected from formula (I) and formula (II).

Description

SUMMARY OF THE INVENTION[0001]The present invention relates to a compound represented by formula (E). The present invention also relates to a compound represented by the formula (E) for use in the treatment or prevention of diseases linked to protein aggregation and / or neurodegenerative diseases. Moreover, the present invention relates to pharmaceutical and diagnostic compositions comprising the compound of the invention as well as to a kit. Furthermore, the present invention relates to a method of imaging deposits of aggregated protein. A kit for preparing a detectably labelled compound of the present invention is also disclosed.[0002]Several documents are cited throughout the text of this specification. The disclosure content of the documents cited herein (including any manufacturer's specifications, instructions, etc.) is herewith incorporated by reference.BACKGROUND OF THE INVENTION[0003]M. Ono et al. (Bioorganic & Medicinal Chemistry 16 (2008) 6867-6872) describe certain beta-a...

Claims

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Application Information

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IPC IPC(8): A61K51/04C07D261/08C07D231/12C07D233/64C07D271/06A61K31/4155A61K31/42A61K31/415A61K31/4164A61K31/4245A61K49/00A61P25/16A61P25/00A61P25/28G01N33/566C07D405/10
CPCC07D207/333C07D231/06C07D231/12C07D413/04C07D261/08C07D271/06C07D405/04C07D233/64A61K31/40A61K31/415A61K31/4155A61K31/4164A61K31/42A61K31/4245A61P21/00A61P21/02A61P25/00A61P25/14A61P25/16A61P25/28A61P43/00A61P3/10G01N33/6896G01N2800/2828
Inventor GIESE, ARMINBERTSCH, UWEKRETZSCHMAR, HANSHABECK, MATHIASHIRSCHBERGER, THOMASTAVAN, PAULGRIESINGER, CHRISTIANLEONOV, ANDREIRYAZANOV, SERGEYWEBER, PETRAGEISSEN, MARKUSGROSCHUP, MARTIN H.WAGNER, JENS
Owner LUDWIG MAXIMILIANS UNIV MUNCHEN
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