Benzyl urea derivatives for activating TGF-beta signaling
Inventors
Tanga, Mary Jean • Beaulieu, Laura Ellen Downs • Wyss-Coray, Anton • Green, Carol • Zhang, Hui • Luo, Jian
Assignees
SRI International Inc • US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-9796674-B2
Publication Date
2017-10-24
Expiration Date
2034-03-14
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Abstract
Compositions and methods for treatment and prevention of disorders and conditions characterized by reduced TGF-B signaling are described. In particular, the compositions and methods are useful for reducing or eliminating the pathologies associated with Alzheimer's disease. The compositions include urea derivatives containing a piperidine, piperidinium, or a piperidin-4-yl methyl; cycloalkyl, aryl, and fluorobenzyl moieties.
Core Innovation
The invention provides derivatives of compounds that act as agonists of TGF-β signaling, with particular focus on derivatives of a compound designated 11H. These compounds have a general formula I, where R1 is a substituted phenyl (especially phenyl substituted with halogen or fluorine), R2 can be —CH2— or —CH═CH(CH2)—, R3 can be a substituted or non-substituted C5 or C6 cycloalkyl or phenyl, and R4 can be —CH2—N-piperidine or N-piperidine. The compounds are pharmaceutically acceptable and may be formulated for delivery to mammalian subjects to treat pathological conditions resulting from or causing deficiencies in TGF-β signaling. The compositions include pharmaceutically acceptable salts such as chlorides or tosylates.
The problem addressed by the invention arises from diseases and conditions characterized by reduced TGF-β signaling, particularly Alzheimer's disease (AD). AD is a common neurodegenerative disorder with no cure, leading to progressive dementia, cognitive deficits, neurodegeneration, and accumulation of amyloid plaques and Aβ in the brain. Current treatments provide only modest symptomatic relief and do not halt disease progression. TGF-β1 is known to protect neurons and reduce amyloid plaque formation and Aβ accumulation, but effective therapeutic agonists to modulate this pathway are lacking.
The invention overcomes these issues by providing small-molecule TGF-β signaling agonists that activate TGF-β pathways in cells and in vivo. The compounds penetrate the central nervous system, activate TGF-β signaling in transgenic reporter mice, and demonstrate neuroprotective effects in cellular and animal models of AD and neurodegeneration. Benefits include reduction in amyloid plaques and Aβ accumulation, neuroprotection against excitotoxicity, improved cognitive function, and reduced neurodegeneration in transgenic AD mouse models.
Claims Coverage
The claims encompass five main inventive features covering TGF-β signaling agonists, their salts, pharmaceutical compositions containing these agonists, and methods of increasing TGF-β signaling activity in cells and in subjects using these agonists. The claims particularly emphasize specific chemical formulae and pharmaceutically acceptable formulations.
Selection of TGF-β signaling agonists based on specific chemical formulas
The agonists, or their pharmaceutically acceptable salts, are selected from a defined group of chemical formulas specified in the claims, which include structural features such as substituted phenyl groups, cycloalkyl or phenyl moieties, and a N-piperidine moiety.
Protonation state and salt forms of the agonists
The agonists can be protonated at the N-piperidine and exist as pharmaceutically acceptable salts such as chloride, tosylate, or trifluoroacetate forms.
Pharmaceutical compositions comprising therapeutically effective amounts of the TGF-β agonists
Compositions include the defined TGF-β signaling agonists together with pharmaceutically acceptable excipients or carriers, enabling administration to subjects for therapeutic purposes.
Methods for increasing TGF-β signaling activity of cells
Methods involve contacting cells with effective amounts of the TGF-β signaling agonists or their pharmaceutically acceptable salts, using compositions formulated for delivery to mammalian cells or subjects.
Use of the agonists in compositions with pharmaceutically acceptable carriers
The methods further include administering compositions comprising the agonists and pharmaceutically acceptable carriers to mammalian subjects to increase TGF-β signaling activity.
Overall, the claims define compounds with specific structural formulae as TGF-β signaling agonists, their pharmaceutically acceptable salts and compositions, and methods of using these compounds to activate TGF-β signaling in cells and mammals, particularly for therapeutic applications.
Stated Advantages
The compounds are able to cross the blood brain barrier and activate TGF-β signaling in the central nervous system.
They reduce or prevent amyloid plaque formation and Aβ accumulation in the brain, addressing key pathologies of Alzheimer's disease.
They provide neuroprotection against Aβ toxicity and excitotoxic neurodegeneration models.
They improve cognitive function and reduce neurodegeneration in transgenic mouse models of Alzheimer's disease.
The compounds exhibit favorable pharmacokinetics such as oral bioavailability, metabolic stability, and minimal cytochrome P450 inhibition, suggesting good drug-like properties.
Tolerability is demonstrated with established maximum tolerated doses and no significant adverse effects in chronic dosing studies.
Documented Applications
Treatment and prevention of disorders and conditions characterized by reduced TGF-β signaling, including neurological disorders.
Use in reducing or eliminating pathologies associated with Alzheimer's disease, including amyloid plaque formation, Aβ accumulation, neurodegeneration, and cognitive deficits.
Neuroprotective applications against excitotoxic injury and Aβ toxicity in vitro and in vivo.
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