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-8686045-B2
Publication Date
2014-04-01
Expiration Date
2026-06-08
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 to a subject an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor molecule. Specifically, the methods relate to administering a small molecule compound that mimics a brain-derived neurotrophic factor (BDNF) β-turn loop, particularly loop 2, to treat disorders mediated by TrkB receptors.
The problem being solved is the difficulty in developing therapeutic agents based on neurotrophins due to their suboptimal pharmacological properties, such as poor stability, low serum half-lives, poor oral bioavailability, restricted central nervous system penetration, and the complexities arising from the triple receptor signaling network increasing chances of adverse effects. Additionally, producing sufficient quantities of pure neurotrophins is technically challenging and ethically problematic when using human fetal cells.
There is an unmet need for small molecule non-peptidyl or peptide agents that mimic key regions of neurotrophin proteins, activate the TrkB receptor specifically, and can be used to treat disorders without the limitations of native neurotrophins. The invention discloses such small molecule compounds, including detailed structural formulas, that facilitate neural cell survival and promote neural function by specifically binding to and modulating TrkB receptor activity.
Claims Coverage
The patent includes one independent claim focusing on a method of treating a disorder using a specific class of small molecule BDNF mimetics that act as agonists or partial agonists of the TrkB receptor.
Use of small molecule mimetics of BDNF β-turn loop 2 as TrkB receptor agonists or partial agonists
The invention covers administering an effective amount of a compound that is an agonist or partial agonist of the TrkB receptor, where the compound is a small molecule mimetic of the BDNF β-turn loop 2, having a specific chemical structure defined as Formula (II).
Treatment of specific neurological disorders using these compounds
The method treats disorders selected from Alzheimer's disease, Huntington's disease, stroke, Rett syndrome, multiple sclerosis, and Parkinson's disease by administering the described small molecule compounds.
Use of specific small molecule structures as treatment agents
The method includes administering compounds of specified chemical structure exemplified in the patent, such as the particular compound identified as Compound 4 (BD2-4), which has been shown to have desirable TrkB agonist or partial agonist activity.
The main inventive features involve the therapeutic use of small molecule mimetics of the BDNF β-turn loop 2 that specifically agonize or partially agonize the TrkB receptor for treating various neurological disorders, with precise structural definitions of the compounds provided.
Stated Advantages
The compounds demonstrate neurotrophic effects similar to BDNF, promoting neural cell survival and neurite outgrowth.
They have high specificity for TrkB receptor activation without activating related receptors TrkA or TrkC, reducing potential side effects.
Some compounds act as partial agonists, offering potential for more controlled modulation of TrkB activity.
They possess improved drug-like properties including predicted blood-brain barrier penetration, stability, and bioavailability compared to native neurotrophins.
The small molecule nature of the compounds facilitates easier production and avoids ethical issues related to sourcing neurotrophins.
Documented Applications
Treatment of neurological disorders such as Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, Rett syndrome, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and others involving neuronal degeneration or dysfunction mediated by TrkB.
Facilitation of neural cell survival and promotion of neural function in in vitro neuronal cultures and in vivo subjects.
Use in models of neurodegenerative diseases including prevention of quinolinic acid-induced striatal neuron death (Huntington's disease model), protection against MPP+-induced death in dopaminergic neurons (Parkinson's disease model), and prevention of amyloid-β-induced neuronal degeneration (Alzheimer's disease model).
Coating of medical devices such as cochlear implants and neural interface devices to promote neural and non-neural cell survival in tissues contacting the device.
Interested in licensing this patent?