Compounds for stabilizing ryanodine receptors from aberrant levels of calcium release

Inventors

Stutzmann, Grace E. • Dahl, Russell • Kaiho, Christopher H.

Assignees

Rosalind Franklin University of Medicine and Science

Abstract

Disclosed herein are methods and compositions comprising compounds capable of normalizing neuronal calcium dyshomeostasis. Also disclosed are methods comprising these compounds for treating neuronal or neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, fronto-temporal dementia, Pick's disease, chronic traumatic encepholopathy, traumatic brain injury, stroke, cerebellar ataxia, multiple sclerosis, Down syndrome, and aging-related CNS disorders.

Core Innovation

The invention discloses methods and compositions comprising novel compounds capable of normalizing neuronal calcium dyshomeostasis by stabilizing ryanodine receptor (RyR) channels, particularly in neurons. These compounds are based on specific chemical scaffolds outlined in the formulas provided within the disclosure and are described as RyR-targeted small molecule compounds. The compounds normalize aberrant endoplasmic reticulum (ER) calcium signaling and aim to preserve synaptic functions, addressing a central pathological mechanism in neurodegenerative diseases.

The core problem being addressed is the lack of effective treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and others. Previous therapeutic targets, such as amyloid precursor protein processing, have not effectively retained cognitive abilities in patients. Aberrant calcium signaling cascades, leading to calcium dyshomeostasis in neurons—specifically involving increased ER calcium release through RyR channels—are directly linked to key features and risk factors of these diseases. Stabilizing ER calcium by targeting RyR channels provides a more direct mechanism to mitigate the progression and symptoms of these neurological disorders.

The invention provides specific compounds of defined structure (with various options and substituent groups) that act as allosteric modulators rather than classical antagonists of RyR channels. These compounds are designed to normalize abnormal calcium signals without broadly blocking physiological calcium function, thus preserving normal neural activity. Methods for preparing these compounds and their use in normalizing neuronal calcium dyshomeostasis, as well as treating neurodegenerative and neurological disorders, are also disclosed.

Claims Coverage

There are two main inventive features disclosed in the independent claims, relating to methods for normalizing neuronal calcium dyshomeostasis and methods for treating neurological or neurodegenerative disorders using specific RyR-stabilizing compounds.

The inventive features of the patent center on the administration of specifically-defined RyR-stabilizing compounds for normalizing neuronal calcium signaling and for treating certain neurodegenerative and neurological diseases.

Stated Advantages

Documented Applications