Methods of facilitating neural cell survival using non-peptide and peptide BDNF neurotrophin mimetics
Inventors
Longo, Frank M. • Massa, Stephen M.
Assignees
University of North Carolina at Chapel Hill • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-9604907-B2
Publication Date
2017-03-28
Expiration Date
2026-06-08
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Abstract
Methods and compounds for treating neurological and other disorders are provided. Included is the administering to a subject in need thereof an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor molecule.
Core Innovation
The invention provides methods and compounds for treating neurological and other disorders by administering an effective amount of a compound that has binding and/or modulation specificity for the TrkB receptor molecule. These compounds include small molecule or peptide mimetics of brain-derived neurotrophic factor (BDNF), particularly those mimicking the BDNF β-turn loop 2, designed to activate the TrkB receptor and promote neural cell survival or function.
The problem being solved arises from limitations in the therapeutic use of native neurotrophins such as BDNF. Native neurotrophins exhibit suboptimal pharmacological properties including poor stability, low serum half-lives, likely poor oral bioavailability, and restricted central nervous system penetration. Furthermore, the large size and pleiotropic effects of neurotrophins raise risks of adverse effects and complicate drug development.
Additionally, the ethical and technical challenges of producing large quantities of pure neurotrophins have hindered therapeutic development. Prior synthetic peptides approximating BDNF effects are too large (approximately 2000 MW) to constitute practical medicinal compounds. There is therefore a need for small molecule (<500 MW) or peptide agents that mimic key neurotrophin regions and can specifically activate TrkB without engaging other receptors like p75NTR or sortilin, thereby reducing undesirable interactions.
Claims Coverage
The patent includes multiple claims, with an independent claim directed to a method of treating a disorder by administering a compound represented by Formula (VII), and a method of facilitating neuronal or other cell survival by contacting a cell with the same compound.
Method of treating a disorder using a specific BDNF mimetic compound
Administering to a subject an effective amount of a compound represented by Formula (VII) that has binding and/or modulation specificity for the TrkB receptor to treat various disorders.
Method of facilitating neuronal or other cell survival using the compound of Formula (VII)
Contacting a neuronal or other cell with a compound represented by Formula (VII) to promote survival or function through TrkB receptor activation.
Formulation of the compound with pharmaceutically acceptable carrier
Formulating the compound of Formula (VII) in a unit dosage form for administration, ensuring proper delivery.
Specification of chemical structure elements in the compound
Defining each L9 and L10 within the compound as C1-C3 alkylene (preferably C2 alkylene) to provide specific molecular configurations for activity and binding.
Identification of treatable disorders with the compound
Targeting disorders including but not limited to Alzheimer's disease, Huntington's disease, Rett syndrome, stroke, multiple sclerosis, and Parkinson's disease for treatment by the compound.
The independent claims chiefly cover methods of treating disorders and promoting cell survival by administration or contact with a small molecule compound having binding and/or modulation specificity for the TrkB receptor, specifically compounds of Formula (VII) with defined structural features, including their formulation and application to several neurological disorders.
Stated Advantages
The compounds demonstrate neurotrophic effects similar to BDNF but with small molecule characteristics conducive to drug development.
They selectively activate the TrkB receptor without activating related receptors TrkA and TrkC, enhancing specificity and potentially reducing side effects.
Some compounds act as partial agonists, providing nuanced modulation of TrkB signaling and therapeutic flexibility.
The compounds protect neurons in various disease models (Huntington's, Parkinson's, Alzheimer's) illustrating broad neuroprotective efficacy.
Documented Applications
Treatment of neurological disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Rett syndrome, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications, motor neuron disease, multiple sclerosis, HIV dementia, peripheral nerve injury, and hearing loss.
Treatment of non-neurological conditions including depression, obesity, metabolic syndrome, pain, and cancer.
Facilitation of neural cell survival and promotion of neural function by contacting neural cells with TrkB mimetics in vitro or in vivo.
Use in stem cell methods to maintain undifferentiated states or induce differentiation by substituting BDNF with the mimetic compounds.
Coating medical devices such as surgical tools, biosensors, cochlear implants, neural interface devices, or synthetic matrices with BDNF mimetics to promote neural or non-neural cell survival in contact tissues or fluids.
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