Derivatives of docosahexaenoylethanolamide and uses thereof
Inventors
Kim, Hee-Yong • Marugan, Juan Jose • Englund, Erika E. • Patnaik, Samarjit
Assignees
US Department of Health and Human Services
Publication Number
US-9422308-B2
Publication Date
2016-08-23
Expiration Date
2033-03-15
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Abstract
The invention provides derivatives of DEA which have increased potency and hydrolysis resistance as compared to DEA, and compositions thereof, as well as methods of using these derivatives to promote neurogenesis, neurite growth and/or length, and/or promote synaptogenesis.
Core Innovation
The invention provides derivatives of docosahexaenoylethanolamide (DEA, also called synaptamide) that exhibit increased potency and resistance to hydrolysis compared to DEA. These derivatives and their compositions are designed to promote neurogenesis, neurite growth and/or length, and synaptogenesis.
The problem addressed by the invention arises from the need for additional DHA derivatives with improved potency and stability. Docosahexaenoic acid (DHA) is an essential fatty acid enriched in the brain that increases neurogenesis, neurite growth, and synaptogenesis. Its derivative, DEA, similarly promotes hippocampal development and synaptic function. However, there is a need for agents with enhanced potency and stability suitable for treating central nervous system (CNS) conditions such as stroke, neurodegenerative diseases, and brain injuries.
The invention provides specific compounds having the formula CH3CH2HC═CHCH2HC═CHCH2HC═CHCH2HC═CHCH2HC═CHCH2HC═CHCH2CH2CO—NR1R2, where NR1R2 is selected as described in Table 1. These synaptamide derivatives demonstrate superior neurogenic activity and resistance to fatty acid amide hydrolase (FAAH) hydrolysis. Methods of using these compounds involve applying them to neurons or neural stem cells to promote neurite growth, synaptogenesis, and neurogenesis in vitro or in vivo, particularly for treating CNS and neurological conditions.
Claims Coverage
The patent includes three independent claims focused on: the compound derivatives, compositions comprising the compounds, and methods of promoting neurite growth and neurogenesis.
Compound derivatives having a specific chemical formula with defined NR1R2 groups
A compound having the formula CH3CH2HC═CHCH2HC═CHCH2HC═CHCH2HC═CHCH2HC═CHCH2HC═CHCH2CH2CO—NR1R2, wherein NR1R2 is selected from specified amine groups as identified in Table 1.
Pharmaceutical compositions comprising the derivatives
Compositions comprising the above compounds and a pharmaceutically acceptable carrier suitable for therapeutic or prophylactic use.
Methods of increasing neurite growth and/or length within mammals
Administering an effective amount of a compound with the defined formula as above to increase neurite growth and/or length in a mammal, including mammals with neurological conditions such as traumatic brain injury, stroke, multiple sclerosis, autism, Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
Methods of increasing neurogenesis within mammals
Administering an effective amount of a compound with the defined formula as above to increase neurogenesis in a mammal, including mammals with the aforementioned neurological conditions.
The claims collectively cover the chemical derivatives of synaptamide, pharmaceutical compositions thereof, and methods using these compounds to promote neurological repair processes such as neurite growth and neurogenesis in mammals suffering from CNS conditions.
Stated Advantages
The derivatives have increased potency compared to synaptamide (DEA).
They demonstrate improved resistance to hydrolysis by fatty acid amide hydrolase (FAAH), enhancing stability.
The compounds promote neurogenesis, neurite growth and/or length, and synaptogenesis effectively at lower dosages than DHA or synaptamide.
They show therapeutic potential for functional improvement after traumatic brain injury as demonstrated in vivo.
Documented Applications
Promoting neurogenesis, neurite growth and/or length, and synaptogenesis in neurons or neural stem cells.
Treatment of central nervous system (CNS) conditions including stroke, neurodegenerative diseases (such as Parkinson's, Huntington's, Alzheimer's, multiple sclerosis, amyotrophic lateral sclerosis), brain injuries, traumatic brain injury, spinal cord injury, peripheral nerve injury, and autism.
Pharmaceutical use in humans and other mammals to enhance cortical and hippocampal development and repair mechanisms.
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