6-substituted estradiol derivatives for use in remyelination of nerve axons
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Publication Number
US-9364486-B2
Publication Date
2016-06-14
Expiration Date
Abstract
Disclosed is a method of remyelinating axons with 6-substituted estradiol compounds of the formulaThe methods can be used to treat a variety of demyelinating diseases.
Core Innovation
The invention provides a method of treating demyelination and/or enhancing remyelination of an axon of a nerve cell in need of remyelination by contacting one or more progenitor cells with an effective amount of a 6-substituted estradiol derivative. The contacting initiates transcription of RNA encoding genes involved in signaling pathways for differentiation of the one or more progenitor cells to one or more cells that form myelin, and the differentiated cells form myelin and enhance remyelination of the axon.
The invention also provides a method of treating a demyelinating disorder in a subject by administering an effective amount of a 6-substituted estradiol derivative and monitoring the subject for remyelination. The 6-substituted estradiol derivative is defined by a formula in which the a ring, R1, R2, R3, R4, R11, X, Y, Z, m, and n are selected according to specified substituent and integer ranges, and includes the respective enantiomers, other stereochemical isomers, tautomers, and pharmaceutically acceptable salts of the compounds.
The disclosure further references pharmaceutical compositions containing 6-substituted estradiol derivative compounds, including racemic and isolated enantiomer forms and specific named compound embodiments including compound 21 and compound 4. In vitro gene-expression profiling and oligodendrocyte differentiation assays demonstrate transcriptional upregulation of myelin-related genes and increased oligodendrocyte maturation/process formation for compounds 4 and 21 relative to controls.
Claims Coverage
Two independent claims are identified. The first covers contacting progenitor cells with a 6-substituted estradiol derivative to initiate differentiation-related transcription and enhance remyelination. The second covers administering a 6-substituted estradiol derivative to a subject for demyelinating disorder treatment followed by monitoring remyelination.
Contacting progenitor cells with a 6-substituted estradiol derivative to initiate differentiation-related transcription and enhance remyelination
Contacting one or more progenitor cells with an effective amount of a 6-substituted estradiol derivative of the defined formula, initiating transcription of RNA encoding genes involved in signaling pathways for differentiation of the one or more progenitor cells to one or more cells that form myelin, differentiating the progenitor cells to the cells that form myelin, and enhancing remyelination of the axon, including the respective enantiomers, other stereochemical isomers, tautomers, and pharmaceutically acceptable salts.
Administering a 6-substituted estradiol derivative for demyelinating disorder treatment and monitoring remyelination
Administering to a subject an effective amount of a 6-substituted estradiol derivative of the defined formula, including variable selections for the a ring, Y, Z, m, and n, and monitoring the subject for remyelination.
Across the independent claims, the core inventive subject matter is the use of defined 6-substituted estradiol derivative compounds to induce differentiation-related transcription leading to myelin-forming cells and enhanced remyelination, and the use of the same structural class for subject treatment with subsequent monitoring of remyelination.
Stated Advantages
Upregulation of myelin-related genes in vitro for compounds 4 and 21 relative to controls.
Increased oligodendrocyte maturation/process formation for compounds 4 and 21 relative to controls.
Enhancing remyelination of the axon of a nerve cell.
Treating demyelination and/or enhancing remyelination.
Documented Applications
Treating demyelination and/or enhancing remyelination of an axon of a nerve cell needing remyelination.
Treating a demyelinating disorder in a subject, with monitoring for remyelination.
Multiple sclerosis is explicitly listed as a demyelinating disorder for treatment.
Other demyelinating and neurological disorders are explicitly listed, including experimental autoimmune encephalomyelitis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leukoencephalopathy, Guillain-Barré Syndrome, central pontine myelinolysis, and leukodystrophies including Krabbe disease, Adrenoleukodystrophy (ALD), Pelizaeus-Merzbacher disease, Canavan disease, and Refsum disease.
In vitro gene-expression profiling and oligodendrocyte differentiation assays demonstrating transcriptional upregulation of myelin-related genes and increased oligodendrocyte maturation/process formation for specific compounds including compound 4 and compound 21.
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