Myricanol derivatives and uses thereof for treatment of neurodegenerative diseases
Inventors
Dickey, Chad • Jinwal, Umesh • Calcul, Laurent • Baker, Bill J. • Lebar, Matthew
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-10287227-B2
Publication Date
2019-05-14
Expiration Date
2033-04-08
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Abstract
The subject invention pertains to myricanol derivatives, therapeutic compositions, and methods for treatment of neurodegenerative diseases, in particular, neurodegenerative diseases associated with abnormal accumulation of protein tau.
Core Innovation
The invention provides myricanol derivatives, therapeutic compositions, and methods for the treatment of neurodegenerative diseases, particularly those associated with abnormal accumulation of protein tau. The compounds include specific myricanol derivatives such as Compound 22 and Compound 23 and their salts, which have been shown to reduce intracellular tau levels effectively.
The problem being addressed relates to neurodegenerative diseases known as tauopathies, where abnormal intracellular aggregation of phosphorylated tau proteins causes pathological features linked to diseases like Alzheimer's disease and Parkinson's disease. Existing therapeutics focus mainly on preventing abnormal phosphorylation or aggregation of tau proteins, but these approaches demonstrate limited efficacy. It has been discovered that the soluble tau intermediates, rather than the aggregated neurofibrillary tangles, are primarily toxic and responsible for cognitive dysfunction. Therefore, agents that degrade, destabilize, or clear aberrant tau intermediates from cells are needed for effective treatment.
The invention solves this problem by providing compounds derived from myricanol that reduce intracellular tau protein levels and thereby treat or ameliorate neurodegenerative diseases associated with abnormal tau accumulation. These compounds target the reduction or clearance of abnormal tau species selectively, preserving normal functional tau. Through administration of these compounds and their pharmaceutical compositions, tau protein levels can be reduced, addressing disease progression and associated symptoms.
Claims Coverage
The claims encompass three main inventive features related to specific myricanol derivatives, their pharmaceutical compositions, and methods of reducing intracellular tau levels for treating neurodegenerative diseases.
Compounds having the chemical structure of formula B or C or salts thereof
This feature covers compounds defined by chemical formula B or C, including specific embodiments such as Compound 23 and Compound 24, representing specific myricanol derivatives structurally characterized by defined substituents.
Pharmaceutical compositions comprising the claimed compounds
This feature covers pharmaceutical compositions containing any of the compounds having formula B, formula C, Compound 23, or Compound 24 in therapeutically effective amounts combined with pharmaceutically acceptable carriers or excipients suitable for administration.
Methods of reducing intracellular tau levels using compounds of formula B
This inventive feature relates to therapeutic methods where an effective amount of a compound having formula B, including Compound 23, is administered to cells, particularly cells within a subject in need, to reduce intracellular tau protein levels, thereby treating tauopathies such as Alzheimer's disease and related neurodegenerative diseases.
Overall, the claims protect specific myricanol derivative compounds defined by formula B or C, their pharmaceutical formulations, and therapeutic methods employing these compounds to reduce intracellular tau protein for treating neurodegenerative tauopathies.
Stated Advantages
The compounds potently reduce levels of tau proteins associated with neurodegenerative diseases, offering a promising therapeutic approach.
The active synthesized myricanol derivatives exhibit low toxicity and do not alter levels of glyceraldehyde 3-phosphate dehydrogenase (GADPH), indicating a favorable safety profile.
The compounds selectively target abnormal tau species, modulating tau clearance while sparing normal functional tau, which may reduce side effects.
Documented Applications
Treatment or amelioration of neurodegenerative diseases associated with abnormal accumulation of protein tau, including Alzheimer's disease and Parkinson's disease.
Reduction of intracellular tau levels in cells comprising protein tau as a method for treating tauopathies.
Use in treatment of various tauopathies such as frontotemporal dementia, progressive supranuclear palsy, Pick's disease, and related neurodegenerative disorders involving tau pathology.
Alleviation or attenuation of symptoms arising from neurodegenerative diseases, including cognitive dysfunction, impaired memory, mental impairment, speech dysfunction, tremor, and rigidity.
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