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 amyotrophic 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.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 14 / 369,624, filed Jun. 27, 2014, as the U.S. National Stage of International Patent Application No. PCT / EP2012 / 076773, filed Dec. 21, 2012, each of which is hereby incorporated by reference in its entirety, and which claim priority to European Patent Application No. 11196121.5, filed Dec. 29, 2011.SEQUENCE LISTING[0002]The sequences listed in the accompanying Sequence Listing are presented in accordance with 37 C.F.R. 1.822. The Sequence Listing is submitted as an ASCII computer readable text file, which is incorporated by reference herein.FIELD[0003]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 amyotrophic lateral sclerosis, in a subject. The invention also provides a pharmaceutical composit...

AI Technical Summary

Benefits of technology

The patent is about a compound that can prevent damage to nerve cells in the brain and spinal cord, which are affected in neurodegenerative diseases. The compound works by blocking a protein called TRPM4, which regulates the influx of certain ions into cells. This blocking action stops or reduces the damage and loss of nerve cells, and can even stop the disease from progressing. The compound can be a molecule that interacts with the TRPM4 protein or an antisense polynucleotide that blocks the gene that encodes the protein. Other examples include RNAi molecules and ribozymes that can target the TRPM4 gene.

Problems solved by technology

Neurodegenerative diseases of the central nervous system (CNS) which cause progressive loss of neuronal structure and function are particularly devastating diseases for the affected patients and their families.

Due to the complexity of the CNS many of these diseases are only poorly understood to date.

It affects approximately 2.5 million individuals worldwide and currently no curative treatment is available.

While the pathophysiological mechanisms leading to neuro-axonal injury during chronic inflammation of the CNS are still ill defined, it has been suggested that chronic CNS inflammation is associated with an increased oxidative stress and release of glutamate, which results in axonal and neuronal injury by inducing mitochondrial dysfunction and increased metabolic demand.

However, the downstream mechanisms, which are initiated by ATP shortage and Ca2+ overload culminating in a sustained influx of cations and eventually leading to neuro-axonal degeneration, remain elusive (Stirling et al.

Expression of the TRPM4 ion channel was up-regulated in capillary epithelial cells after spinal cord injury, leading to capillary leakiness and failure of capillary integrity.

However, functional neuronal expression and a contribution of TRPM4 to neurodegeneration in diseases like MS have thus far not been shown or otherwise suggested.

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