Thalidomide analogs and methods of use
Inventors
Greig, Nigel H. • Luo, Weiming • Tweedie, David • Vargesson, Neil • Beedie, Shaunna • Figg, William Douglas
Assignees
University of Aberdeen • US Department of Health and Human Services
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Publication Number
US-11440880-B2
Publication Date
2022-09-13
Expiration Date
2036-09-29
Abstract
Thalidomide analogs and methods of using the thalidomide analogs are disclosed. Some embodiments of the disclosed compounds exhibit anti-angiogenic and/or anti-inflammatory activity. Certain embodiments of the disclosed compounds are non-teratogenic.
Core Innovation
This disclosure concerns thalidomide analogs, particularly identification of non-teratogenic analogs, and methods of use. The invention provides thalidomide analogs and pharmaceutically acceptable salts thereof, along with pharmaceutical compositions comprising these analogs, which possess anti-angiogenic and/or anti-inflammatory activity. Certain embodiments of the disclosed compounds are non-teratogenic, as demonstrated by zebrafish and chicken embryo assays.
The problem being solved is the teratogenicity of thalidomide and its analogs. Thalidomide was originally marketed as a non-toxic sedative but was withdrawn due to its potent teratogenic side effects causing severe congenital abnormalities. Although thalidomide exhibits beneficial anti-inflammatory and anti-angiogenic properties—such as inhibiting tumor necrosis factor alpha (TNF-α) synthesis and angiogenesis—its teratogenic effects limit clinical use. Existing thalidomide analogs often retain teratogenicity, creating a need for analogs that maintain clinical efficacy with reduced or no teratogenicity, improved potency, and fewer side effects.
The disclosed analogs have defined chemical structures according to a general formula I with specific substituents and ring formations. Some embodiments are non-teratogenic at concentrations relevant for therapeutic activity and can possess anti-inflammatory properties without anti-angiogenic effects, anti-angiogenic properties without anti-inflammatory effects, or both anti-inflammatory and anti-angiogenic properties. Methods of use include inhibiting TNF-α activity, TNF-α synthesis, angiogenesis, and/or inflammation by contacting cells or administering therapeutically effective amounts to subjects. The disclosure also covers pharmaceutical compositions and methods of combination therapy with other agents.
Claims Coverage
The patent presents two main independent claims focused on the thalidomide analog compounds and their use in inhibiting biological activities.
Thalidomide analog compounds with defined chemical structures
The claim covers thalidomide analogs or pharmaceutically acceptable salts thereof having structures according to generalized formula I defined in the patent, including specific substituents, ring structures, and stereochemical configurations with detailed provisos on their components, enabling biological activity and non-teratogenicity.
Pharmaceutical compositions comprising thalidomide analogs
The claim covers compositions including a thalidomide analog or pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier, suitable for therapeutic administration.
Methods for inhibiting TNF-α activity, synthesis, angiogenesis, and inflammation
Claims methods of contacting cells or administering therapeutically effective amounts of thalidomide analogs to subjects to inhibit TNF-α activity, TNF-α synthesis, angiogenesis, inflammation, or combinations thereof. This includes use of particular compounds identified in the patent and various administration routes.
Methods for treating inflammatory and autoimmune disorders
Some claims specify using the thalidomide analogs possessing anti-inflammatory properties to inhibit inflammation or treat inflammatory disorders, including neurodegenerative diseases, by administering therapeutically effective doses to subjects.
Combination therapies with second therapeutic agents
Claims methods where thalidomide analogs are administered in combination with second therapeutic agents such as anti-cancer, anti-angiogenic, or anti-inflammatory agents, either separately or as combined compositions.
In sum, the patent claims analogs of thalidomide with precise structural definitions, pharmaceutical compositions containing them, and methods of their therapeutic use to inhibit TNF-α, inflammation, and angiogenesis, including combination therapies, providing non-teratogenic alternatives to existing thalidomide compounds.
Stated Advantages
Certain disclosed thalidomide analogs exhibit anti-inflammatory and/or anti-angiogenic properties while being non-teratogenic.
Some analogs are effective at therapeutically relevant doses and can be non-neurotoxic at those doses.
The analogs offer potential for improved potency and fewer side effects compared to current thalidomide analogs.
The compounds can pass the blood-brain barrier, enabling treatment of central nervous system conditions involving inflammation.
Documented Applications
Treatment of disorders mediated by TNF-α, angiogenesis, and/or inflammation including inflammatory, autoimmune, and neurodegenerative disorders.
Use in inhibiting pathological angiogenesis in diseases such as cancer (including multiple myeloma), ocular angiopathies, psoriasis, hemangiomas, and wound granulation.
Treatment of neurodegenerative and neuroinflammatory disorders including Alzheimer's disease, Parkinson's disease, traumatic brain injury, stroke, ALS, multiple sclerosis, and others.
Use in reducing neuroinflammation and delaying progression of diseases involving chronic inflammation.
Combination therapies with anti-cancer agents, anti-angiogenic agents, and anti-inflammatory agents.
Potential treatment of sarcopenia and other systemic inflammatory disorders.
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