6-substituted estradiol derivatives for use in remyelination of nerve axons
Inventors
Yarger, James G. • Nye, Steven H.
Assignees
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Publication Number
US-9636348-B2
Publication Date
2017-05-02
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 relates to a method of treating demyelination and/or enhancing remyelination of an axon of a nerve cell that is in need of remyelination. The method provides a 6-substituted estradiol derivative compound of a defined formula, including the respective enantiomers, other stereochemical isomers, tautomers, and pharmaceutically acceptable salts.
One or more progenitor cells are contacted with an effective amount of the compound so that the progenitor cells differentiate into one or more cells that form myelin, thereby enhancing remyelination of the axon of a nerve cell. The compounds are described with defined ring substitutions and include racemic mixture and substantially enantiomer-purified variants, together with derivative forms such as hydroxyl, methoxymethyl, hydroxymethyl, oxo, diol, aminooxy, and ester or hydrogen sulfate forms.
The invention also covers treating a demyelinating disorder in a subject by administering an effective amount of a 6-substituted estradiol derivative of the defined formula and monitoring the subject for remyelination. Monitoring is described in terms of improvement in symptoms of a demyelinating disorder, and the scope includes demyelinating disorders and neurologic conditions, including multiple sclerosis, multiple leukodystrophies, experimental autoimmune encephalomyelitis, acute disseminated encephalomyelitis, transverse myelitis, and progressive multifocal leukoencephalopathy.
Claims Coverage
The partial content includes two independent claims. Together, they cover a progenitor-cell differentiation approach to enhance remyelination of an axon using defined 6-substituted estradiol derivative compounds, and a subject-treatment method for demyelinating disorders using the same compound class with monitoring for remyelination.
Progenitor-cell differentiation to enhance remyelination
A method of treating demyelination and/or enhancing remyelination of an axon of a nerve cell, comprising providing a compound of a defined formula with substituent selections, including enantiomers, other stereochemical isomers, tautomers and pharmaceutically acceptable salts, and contacting one or more progenitor cells with an effective amount of the compound to differentiate the progenitor cells into one or more cells that form myelin, thereby enhancing remyelination of the axon of a nerve cell.
Treating a demyelinating disorder by administering and monitoring
A method of treating a demyelinating disorder in a subject comprising administering to the subject an effective amount of a 6-substituted estradiol derivative of the defined formula, including enantiomers, other stereochemical isomers, tautomers and pharmaceutically acceptable salts, and monitoring the subject for remyelination.
Across the two independent claims, the central inventive concept is the use of specifically defined 6-substituted estradiol derivative compounds with specified stereochemical and structural constraints to drive differentiation of progenitor cells into myelin-forming cells to enhance remyelination, and to treat demyelinating disorders with remyelination monitored after administration.
Stated Advantages
Enhancing remyelination of the axon of a nerve cell.
Treating demyelination.
Differentiating one or more progenitor cells to one or more cells that form myelin.
Monitoring for remyelination via improvement in symptoms of a demyelinating disorder.
Promoting myelin formation through binding to ER-α and ER-β and upregulating gene transcription in precursor/progenitor cells.
Documented Applications
Treatment of demyelination and/or enhancing remyelination of an axon of a nerve cell in need of remyelination by contacting progenitor cells with a defined 6-substituted estradiol derivative to form myelin-forming cells.
Treatment of a demyelinating disorder in a subject, followed by monitoring the subject for remyelination, with remyelination assessed via improvement in symptoms.
Included disorder examples listed in dependent claim scope, including multiple sclerosis, multiple leukodystrophies, experimental autoimmune encephalomyelitis, acute disseminated encephalomyelitis, transverse myelitis, and progressive multifocal leukoencephalopathy.
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