Pharmaceutical formulations comprising 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-8916556-B2
Publication Date
2014-12-23
Expiration Date
2026-04-03
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Abstract
Methods and compounds for treating neurodegenerative and other disorders. Included is the administering to a subject in need thereof an effective amount of a compound having binding specificity for a p75NTR receptor molecule. Enhanced survival of neural and other cells has been observed.
Core Innovation
The invention relates to methods and compounds for treating neurodegenerative and other disorders by administering to a subject an effective amount of a compound having binding specificity for a p75NTR receptor molecule. These compounds act as neurotrophin mimetics and have been shown to enhance the survival of neural and other cells expressing the p75NTR receptor.
The problem being addressed is the limited therapeutic options for neurodegenerative disorders due to difficulties associated with administering neurotrophins themselves. Neurotrophins exhibit poor pharmacological properties such as low serum half-life, poor oral bioavailability, and limited central nervous system penetration. Furthermore, the dual receptor signaling network of neurotrophins increases adverse effects, and technical and ethical constraints hamper the production and use of neurotrophins as therapies.
The invention provides compounds that mimic neurotrophin β-turn loops, particularly loop 1 of nerve growth factor (NGF), which bind specifically to p75NTR receptor molecules. These compounds facilitate survival signaling and inhibit proNGF-induced cell death in cells expressing p75NTR. The compounds can be small molecules or peptides, and derivatives thereof, which have desirable pharmacological properties including improved hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation compared to the parent compounds.
Claims Coverage
The claims include two independent claims directed to pharmaceutical formulations comprising specific active compounds with defined structures. The inventive features focus on the chemical structures of the active ingredients and their inclusion in pharmaceutical formulations.
Pharmaceutical formulations comprising specified compounds
Pharmaceutical formulations comprising a unit dose of an active ingredient selected from compounds having specific chemical structures, including compounds of Formula (I) or (II) with defined linking groups, substituents, and pharmaceutically acceptable salts, combined with a pharmaceutical grade carrier.
Formulations as liquid or solid dosage forms
The pharmaceutical formulations are further characterized by being prepared as liquid solutions, suspensions, emulsions, tablets, pills, or capsules suitable for administration, including administration to humans.
The claims cover pharmaceutical formulations comprising compounds having specific chemical structures that bind to the p75NTR receptor, formulated in pharmaceutically acceptable carriers in various dosage forms suitable for human administration.
Stated Advantages
The compounds promote enhanced survival of neural and other cells expressing p75NTR.
The compounds exhibit favorable drug-like features including improved bioavailability and blood-brain barrier penetration compared to native neurotrophins.
The compounds can selectively activate survival signaling pathways associated with p75NTR without activating Trk receptors, potentially reducing adverse effects.
The compounds inhibit proNGF-induced cell death in certain cell types, such as mature oligodendrocytes.
Some compounds block amyloid-beta-induced neural degeneration and prevent hair loss in preclinical models.
Documented Applications
Treatment of neurodegenerative disorders including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, Pick's disease, multiple sclerosis, and other conditions involving degeneration or dysfunction of p75NTR-expressing cells.
Facilitation of survival of neural cells such as septal, hippocampal, cortical, sensory, sympathetic, motor neurons, as well as oligodendrocytes and hair follicle cells.
Prevention of neurodegeneration caused by chemotherapy or pathological conditions.
Inhibition of proNGF-induced apoptotic death in mature oligodendrocytes.
Blocking amyloid-beta induced neural degeneration relevant to Alzheimer's disease models.
Prevention of hair loss in middle-aged mice, indicating potential for treatment of alopecia.
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