Chemical model of a neurodegenerative disease, method for preparation and uses of same

Patent metadata

Field	Value
Publication number	US-9744250-B2
Application number	US-201314443499-A
Country	US
Kind code	B2
Filing date	Nov 19, 2013
Priority date	Nov 19, 2012
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The invention concerns the use of pyridinium furosemide or one of the derivatives, analogs, salts, metabolites, or prodrugs thereof in the preparation of a chemical model of a neurodegenerative disease, preferably Parkinson's disease. The invention also concerns the corresponding chemical model and the uses of same, in particular in screening tests for identifying drug candidates.

First claim

The invention claimed is:

1. A method for preparing a chemical model of a synucleinopathy, comprising a step of placing a cell system in contact with a compound selected from the group consisting of:
(i) furosemide pyridinium; and
(ii) a compound of formula (I)

wherein:
R 1 represents a hydrogen atom, a C 1 -C 4 alkyl, a halogen atom, —OH, —CN, —CF 3 , —C(═O)NH 2 , —C(═O)O − , or —C(═O)O—R 5 where R 5 represents H or a C 1 -C 4 alkyl,
R 2 is a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 6 , where R 6 represents H or a C 1 -C 4 alkyl,
R 3 is H, a halogen atom, a C 1 -C 4 alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 7 where R 7 represents H or a C 1 -C 4 alkyl, and
R 4 represents a hydrogen atom, —OH, or —OCH 3 ,

or a pharmaceutically acceptable salt thereof, wherein the cell system is derived from nervous tissue or is of neuronal origin,
and whereby the chemical model of a synucleinopathy is obtained.

2. The method of claim 1 , wherein the synucleinopathy is Parkinson's disease.

3. The method of claim 1 , wherein the cell system is selected from the group consisting of nervous tissue, an organotypic culture obtained from brain tissue, a culture of nerve cells, a primary neuron culture, and a cell line of neuronal origin.

4. The method of claim 1 , wherein the cell system is a cell line selected from the group consisting of the cell lines SH-SY5Y, SK-N-MC, and PC12.

5. The method of claim 1 , wherein the compound is furosemide pyridinium.

6. A chemical model of a synucleinopathy obtained according to the method of claim 1 .

7. A method for evaluating, screening, or selecting a compound for the treatment or prevention of a synucleinopathy, said method comprising:
a) placing a cell system in contact with a compound selected from the group consisting of:
(i) furosemide pyridinium; and
(ii) a compound of formula (I)

wherein:
R 1 represents a hydrogen atom, a C 1 -C 4 alkyl, a halogen atom, —OH, —CN, —CF 3 , —C(═O)NH 2 , —C(═O)O − , or —C(═O)O—R 5 where R 5 represents H or a C 1 -C 1 alkyl,
R 2 is a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 6 , where R 6 represents H or a C 1 -C 4 alkyl,
R 3 is H, a halogen atom, a C 1 -C 4 alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 7 where R 7 represents H or a C 1 -C 4 alkyl, and
R 4 represents a hydrogen atom, —OH, or —OCH 3 ,

or a pharmaceutically acceptable salt thereof, wherein the cell system is derived from nervous tissue or is of neuronal origin,
b) placing said cell system in contact with the test compound, and
c) detecting or quantifying a marker characteristic of the synucleinopathy to determine the effectiveness of the test compound for reducing the marker characteristic of the synucleinopathy,

wherein step b) may be implemented simultaneously, before, or after step a), or may overlap step a).

8. The method of claim 7 , wherein the compound is furosemide pyridinium.

9. The method of claim 7 , wherein:
said cell system is selected from the group consisting of nervous tissue, an organotypic culture obtained from brain tissue, a culture of nerve cells, and a cell line of neuronal origin, and
said marker is selected from the group consisting of an intracellular accumulation of a synuclein, a marker of apoptotic cell death, a decrease in the cell survival rate, a decrease in the activity of the mitochondrial respiratory chain, and combinations thereof.

10. A kit for implementing a method for evaluating, screening, or selecting a compound intended for the treatment or prevention of a synucleinopathy, or for the preparation of a chemical model of a synucleinopathy, comprising:
a compound selected from the group consisting of:
(i) furosemide pyridinium; and
(ii) a compound of formula (I)

wherein:
R 1 represents a hydrogen atom, a C 1 -C 4 alkyl, a halogen atom, —OH, —CN, —CF 3 , —C(═O)NH 2 , —C(═O)O − , or C(═O)O—R 5 where R 5 represents H or a C 1 -C 4 alkyl,
R 2 is a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 6 where R 6 represents H or a C 1 -C 4 alkyl,
R 3 is H, a halogen atom, a C 1 -C 4 alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 7 where R 7 represents H or a C 1 -C 4 alkyl, and
R 4 represents a hydrogen atom, —OH, or —OCH 3 ,

or a pharmaceutically acceptable salt thereof and
a cell system selected from nervous tissue and a cell or a cell culture from nervous tissue or of neuronal origin, to be placed in contact with the compound in order to obtain said chemical model.

Assignees

• Centre Nat Rech Scient
• Univ Paris-Est Creteil Val De Marne

Inventors

• Martens Thierry
• Rivard Michaël
• Laurencé Céline
• Morin Christophe
• Lehri-Boufala Sonia
• Zeghbib Narimane

Classifications

• C07D213/20

  Quaternary compounds thereof · CPC title

• G01N33/6893

  related to diseases not provided for elsewhere · CPC title

• A61K49/0008 Primary

  Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure · CPC title

• G01N33/5058

  Neurological cells · CPC title

• C07D213/65

  attached in position 3 or 5 · CPC title