Compounds for activating TGF-β signaling
Inventors
Wyss-Coray, Anton • Tanga, Mary J.
Assignees
SRI International Inc • US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-8097645-B2
Publication Date
2012-01-17
Expiration Date
2028-10-10
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Abstract
Compositions and methods for treatment and prevention of disorders and conditions characterized by reduced TGF-β signaling are described.
Core Innovation
The invention provides compositions and methods for the treatment and prevention of disorders and conditions characterized by reduced TGF-β signaling. The compositions include small-molecule, bioactive compounds that can modulate and activate TGF-β signaling, including TGF-β agonists capable of crossing the blood brain barrier (BBB). Such compounds are exemplified by three lead molecules (3A, 11H, and 5E) and their analogs, with defined chemical structures and demonstrated biological activity in vitro and in vivo.
The problem addressed involves the need for more effective pharmaceutical compounds for treating diseases and conditions linked to reduced TGF-β signaling, such as stroke, heart disease, bone loss, cancer, multiple sclerosis, wound healing, inflammation, and neurodegenerative disorders including Alzheimer's disease. TGF-β signaling plays crucial roles in cellular survival, apoptosis, proliferation, differentiation, and inflammation regulation. Dysregulation of this pathway is implicated in various pathologies, yet effective small-molecule activators of TGF-β signaling suitable for therapeutic use are lacking.
Claims Coverage
The patent includes one independent claim focusing on a class of chemical compounds with specific structural features designed to activate TGF-β signaling, along with pharmaceutical compositions containing such compounds.
Compounds having a defined chemical structure that act as TGF-β agonists
A compound defined by a central core structure with substituents R, R1, and R2, where R is selected from hydrogen, halo, alkyl, and substituted alkyl groups, and R1 and R2 have specific substituent options including alkyl, allyl, ether, aromatic, substituted aromatic, branched alkyl, and cyclic alkyl groups. The compounds include various specifically claimed embodiments with particular substituents, demonstrating modulation of TGF-β signaling.
Pharmaceutical compositions comprising the claimed compounds
Pharmaceutical compositions containing one or more of the claimed compounds combined with pharmaceutically acceptable additives such as carriers, binders, disintegrating agents, surfactants, antioxidants, and lubricants. These compositions can be formulated into tablets, capsules, or liquids suitable for oral administration.
The claims focus on chemical compounds with specific substituent patterns that serve as TGF-β agonists, and pharmaceutical compositions containing these compounds for therapeutic use, particularly formulated for oral delivery.
Stated Advantages
The small-molecule TGF-β agonists can cross the blood brain barrier and activate TGF-β signaling in vivo, including in neurons of the brain.
These compounds provide neuroprotection against toxic insults such as amyloid beta (Aβ) oligomers, potentially reducing neuron death in neurodegenerative diseases.
The agonists can reduce amyloid plaque formation and overall Aβ accumulation in models of Alzheimer's disease, indicating therapeutic potential.
The small-molecule agonists mimic TGF-β1 signaling pathways but have distinct gene expression profiles that may confer additional clinical advantages, such as effects on vascular remodeling.
The invention enables formulation of orally bioavailable pharmaceutical compositions with favorable pharmacokinetic properties.
Documented Applications
Treatment and prevention of diseases and conditions characterized by reduced TGF-β signaling, including stroke, heart disease, bone loss, cancer, multiple sclerosis, wound healing, inflammation, and neurological disorders.
Treatment and prevention of neurodegenerative disorders, including Alzheimer's disease and diseases characterized by amyloid plaque deposition and Aβ accumulation.
Use in animal models of excitotoxic injury and neurodegeneration for assessing neuroprotection and therapeutic efficacy.
Monitoring and modulation of TGF-β signaling activity in vivo, including in transgenic reporter mice models.
Potential treatment of other amyloidosis-related diseases such as localized and systemic amyloidosis, familial Mediterranean fever, familial British dementia, familial amyloid polyneuropathy, Creutzfeldt-Jakob disease, Parkinson's disease, frontotemporal dementia, and other neurodegenerative dementias.
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