Inhibitor of trpm-4 ion channel for treating or preventing neurodegeneration

Abstract

The invention relates to a compound which is effective in inhibiting the function of the TRPM4 ion channel and the use of such compound in treating or preventing a neurodegenerative disease, such as Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, or a myotrophic lateral sclerosis, in a subject. The invention also provides a pharmaceutical composition comprising a TRPM4 inhibitory compound. The invention further relates to in vitro methods for identifying pharmaceutically active compounds that are useful for treating or preventing a neurodegenerative disease.

1 . Compound which is effective in inhibiting the function of a TRPM4 ion channel for use in a method of treating or preventing a neurodegenerative disease in a subject. 
     
     
         2 . Compound for use according to  claim 1 , wherein said neurodegenerative disease is associated with glutamate excitotoxicity. 
     
     
         3 . Compound for use according to  claim 1 , wherein said neurodegenerative disease is selected from the group consisting of Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. 
     
     
         4 . Compound for use according to  claim 3 , wherein said neurodegenerative disease is Multiple Sclerosis. 
     
     
         5 . Compound for use according to  claim 1 , wherein the compound is selected from the group consisting of glibenclamide, 9-phenanthrol, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, non-steroidal estrogen, phytoestrogen, zearalenone, 5-butyl-7-chloro-6-hydroxybenzo[c]-quinolizium chloride, flufenamic acid, and spermine. 
     
     
         6 . Compound for use according to  claim 1 , wherein the compound is to be administered in an amount from 1.0 μg/kg body weight to 5,000 μg/kg body weight. 
     
     
         7 . Pharmaceutical composition comprising a compound according to  claim 1  for use in a method of treating or preventing a neurodegenerative disease in a subject. 
     
     
         8 . Pharmaceutical composition according to  claim 7 , which further comprises at least one excipient, diluent, carrier and/or at least one additional pharmaceutically active compound which is useful in the treatment of a neurodegenerative disease. 
     
     
         9 . In vitro method for identifying a pharmaceutically active compound for treating or preventing a neurodegenerative disease in a subject, comprising
 (a) contacting a candidate compound with a functional TRPM4 ion channel;   (b) detecting whether said candidate compound interferes with the function of the TRPM4 ion channel;   wherein a compound which inhibits the function of the TRPM4 ion channel is suitable for treating or preventing said neurodegenerative disease.   
     
     
         10 . In vitro method for identifying a pharmaceutically active compound for treating or preventing a neurodegenerative disease in a subject, comprising
 (a) contacting a candidate compound with a cell that expresses a functional TRPM4 ion channel;   (b) detecting whether said candidate compound decreases the transcription of the TRPM4 gene and/or the translation of the TRPM4 mRNA;   wherein a compound which decreases the transcription of the TRPM4 gene and/or the translation of the TRPM4 mRNA is suitable for treating or preventing said neurodegenerative disease.   
     
     
         11 . Method of  claim 9 , wherein said neurodegenerative disease is associated with glutamate excitotoxicity. 
     
     
         12 . Method of  claim 11 , wherein said neurodegenerative disease is selected from the group consisting of Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. 
     
     
         13 . Method of  claim 12 , wherein said neurodegenerative disease is Multiple Sclerosis. 
     
     
         14 . Use of
 (a) a polypeptide comprising the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2 or a variant thereof having at least 80% sequence identity to the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2; or   (b) a polynucleotide encoding a polypeptide of (a) or the complement thereof   for identifying a pharmaceutically active compound for treating or preventing a neurodegenerative disease.   
     
     
         15 . Use of  claim 14 , wherein said neurodegenerative disease is selected from the group consisting of Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, preferably Multiple Sclerosis. 
     
     
         16 . Method of  claim 10 , wherein said neurodegenerative disease is associated with glutamate excitotoxicity. 
     
     
         17 . Method of  claim 16 , wherein said neurodegenerative disease is selected from the group consisting of Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. 
     
     
         18 . Method of  claim 17 , wherein said neurodegenerative disease is Multiple Sclerosis.