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

[0012]Thus, in a first aspect the invention relates to a 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. More specifically, the invention relates to such an inhibitory compound for use in a method of preventing neuronal damage and / or loss in a subject suffering from a neurodegenerative disease. As used herein, the “function of a TRPM4 ion channel” means the capability of the protein to regulate the influx of ions into the cell, in particular the influx of cations such as Nat Accordingly, a “functional” TRPM4 ion channel refers to a channel protein that effectively regulates the influx of ions, such as Na+, into the cell The present invention is hence useful for treating or ameliorating the effects of neurodegenerative diseases which are associated with TRPM4-mediated cytotoxicity.

[0013]The compounds of the present invention effectively prevent damage and / or loss of neurons in the nervous system (NS) of a subject, preferably in the central nervous system (CNS) of a subject. As used herein, the NS is to be understood as being composed of the CNS and the peripheral nervous system. Further, as used herein, the CNS is to be understood as containing the brain and the spinal cord. In a preferred embodiment, the compounds of the invention are administered for preventing damage and / or loss of neurons in the brain. In a further embodiment, progressive damage and / or loss of neurons may be halted by administration of the compounds of the invention. Halting the damage and / or the loss of neurons means that the pathological processes of the neurodegenerative disease which finally result in damage and / or loss of neurons are stopped or at least reduced.

[0021]The compounds which are contemplated herein for treating and / or preventing a neurodegenerative disease are effective in inhibiting the function of the TRPM4 ion channel. This means that the compounds effectively reduce the extent of membrane current that occurs due to the influx of cations upon opening of the channel. In a preferred embodiment, the compound decreases the TRPM4 ion channel activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the activity in the absence of the compound. In a particularly preferred embodiment, the inhibitory compound blocks the TRPM4 ion channel, i.e. the channel is completely deactivated so that there is no detectable influx of cations, such as Nat The compounds preferably act by interacting with or binding to the TRPM4 protein, thereby preventing the sterical changes in the channel protein that occur upon opening of the channel, e.g. in response to an increase in the intracellular Ca2+ concentration. Compounds that actively bind to TRPM4 may bind to the extracellular, the intracellular or the transmembrane part of the TRPM4 ion channel protein.

[0024]The TRPM4-inhibitory compound of the invention can be derived from different groups of molecules. For example, TRPM4-inhibitory compounds can include antisense polynucleotides which bind to the gene encoding the TRPM4 ion channel and block transcription, RNA processing and / or translation of said gene. The antisense molecules can be RNA or DNA molecules. Also, the TRPM4-inhibitory compound of the invention can be a RNA molecule which exerts its effect by RNA interference. Examples for such compounds are RNAi molecules and siRNA molecules that are capable of blocking translation of the TRPM4-encoding mRNA. Alternatively, the TRPM4-inhibitory compound of the invention can be a ribozyme that cleaves the TRPM4-encoding mRNA. Other classes of molecules which may give rise to suitable TRPM4-inhibitory compounds include peptides, antibodies and antibody fragments. Peptides that bind and interfere with the TRPM4 channel protein may be conveniently screened in random peptide libraries.

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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