Dream neuronal calcium sensor-modulating compounds, and therapeutic uses thereof
Inventors
GUTIÉRREZ RODRÍGUEZ, Marta • CERCOS PITA, Pilar • HERRANZ HERRANZ, MARÍA ROSARIO • GARCÍA LÓPEZ, MARÍA TERESA • VALENZUELA MIRANDA, MARÍA CARMEN • Naranjo Orovio, José Ramón • Mellstrom, Britt • GONZÁLEZ PÉREZ, Paz • MARTÍN MARTÍNEZ, MARÍA MERCEDES • DOPAZO SANTOS, José Manuel
Assignees
Consejo Superior de Investigaciones Cientificas CSIC • Universidad Autonoma de Madrid • Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas CIBERNED
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Publication Number
US-10526276-B2
Publication Date
2020-01-07
Expiration Date
Abstract
The present invention relates to a group of compounds with a structural nucleus derived from phenylacetamide, having the following formula (I): that can modulate the DREAM neuronal calcium sensor. Consequently, the present invention also relates to the use of these compounds for the treatment or prevention of disorders or diseases in which DREAM levels are above or below physiologically normal levels.
Core Innovation
The invention relates to phenylacetamide-derived DREAM neuronal calcium sensor modulators defined by a broad structural formula (I) that includes variable aryl substituents (R1–R3), an amide/ester-containing linker region (X), and additional substituents (R4–R8, Y). The disclosed compounds include pharmaceutically acceptable salts, solvates, and isomers, including enantiomers, of the defined structures, and the modulation concept is associated with DREAM neuronal calcium sensor modulation.
The problem addressed is disorders in which DREAM expression is deregulated. The disclosed approach is intended to treat or prevent disorders where DREAM expression levels are altered, including neurodegenerative, cognitive, sensory, inflammatory/auto-inflammatory disorders, and other disorder categories listed in the disclosure. Specific disorders exemplified include Alzheimer’s disease and other dementias, schizophrenia, Huntington’s disease, dyskinesia, depression, Down syndrome disorders, chronic pain, neuropathic pain, allodynia, atherosclerosis, type-2 diabetes, rheumatoid arthritis, gout, and acute respiratory distress syndrome.
The document supports the modulation concept with example compounds and experimental observations. Patch-clamp assays measuring DREAM-mediated modulation of Kv4.3 currents are described using Kv4.3 and Kv4.3+DREAM CHO cell systems, where some compounds show selective inhibition of DREAM-mediated modulation and others show non-selective behavior. Neuroprotection is also described using Q111DR cells, where reduced LDH release after H2O2 exposure and reduced caspase-3 activation after staurosporine exposure are reported, including a noted lowest caspase-3 activation for compound (62).
Claims Coverage
The partial claim set includes one independent claim defining the structural scope for phenylacetamide-derived DREAM neuronal calcium sensor modulators, together with dependent claims that include formulation and use in treating DREAM-expression-related diseases. The independent claim coverage is grounded in the listed substituted aromatic carboxylic acid/amides/benzoate structures and their inclusion as compounds of the claim group.
Selected substituted aromatic carboxylic acid/amides/benzoate compounds for DREAM neuronal calcium sensor modulation
A compound selected from the group consisting of specific substituted aromatic structures comprising 2-[...acetylamino]benzoic acids and related derivatives, 2-[...propanoylamino]benzoic acids, selected naphthoic acid derivatives, and N-(benzoylphenyl)acetamide variants, including specified chloro/dichloro/fluoro/bromo/dihydroxy/ethynyl and aryl substituent patterns and specified benzoate and benzamide forms.
Overall, the provided independent claim covers a defined set of specific substituted aromatic carboxylic acid/amides/benzoate compounds as modulators of DREAM neuronal calcium sensor modulation, while the dependent claims in the family further ground use as pharmaceutical compositions and as treatment for disorders associated with altered DREAM protein expression levels.
Stated Advantages
Compounds are described as modulating DREAM-mediated modulation of Kv4.3 currents, including some selective inhibition of DREAM-mediated modulation.
Neuroprotection is described, including reduced LDH release after H2O2 exposure in Q111DR cells and reduced caspase-3 activation after staurosporine exposure.
Documented Applications
Treatment or prevention of disorders where DREAM expression is deregulated, including neurodegenerative disorders (e.g., Alzheimer’s disease and other dementias, Huntington’s disease), cognitive disorders, sensory disorders, inflammatory and auto-inflammatory diseases, and other specified disorder categories.
The listed disorder examples explicitly include schizophrenia, dyskinesia, depression, Down syndrome disorders, chronic pain, neuropathic pain, allodynia, atherosclerosis, type-2 diabetes, rheumatoid arthritis, gout, and acute respiratory distress syndrome.
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