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-10730835-B2
Publication Date
2020-08-04
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 invention discloses thalidomide analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions including these analogs. The analogs exhibit anti-angiogenic and/or anti-inflammatory activities, with certain embodiments being non-teratogenic, as demonstrated in zebrafish and chicken embryo assays at concentrations ranging from 10-200 μg/mL. The compounds modulate tumor necrosis factor alpha (TNF-α) activity and synthesis as well as angiogenesis and inflammation. The invention also encompasses methods of using these analogs to inhibit TNF-α activity, angiogenesis, and inflammation in cells or subjects, optionally in combination with other therapeutic agents.
The problem addressed by this invention is the known teratogenicity of thalidomide and its analogs, which limits their clinical utility despite their anti-inflammatory and anti-angiogenic efficacy. Thalidomide historically caused severe congenital abnormalities, including limb reduction defects, when administered to pregnant women. Analogs of thalidomide are also commonly teratogenic. Therefore, there is a need for thalidomide analogs that retain clinical potential—specifically anti-inflammatory and anti-angiogenic properties—while avoiding teratogenicity. Additionally, there is a need for compounds with improved potency and reduced side effects relative to currently used analogs.
The disclosed analogs are structurally defined by general formula I, with detailed substituents and stereochemistry, and are synthesized as characterized compounds. Experimental data establish their non-teratogenicity and biological activities using in vivo zebrafish and chicken embryo models, cell-based assays for TNF-α inhibition, anti-angiogenic activity in rat aortic ring and human umbilical vein endothelial cell (HUVEC) assays, and in vivo efficacy in mouse tumor xenografts. Specific compounds within the disclosure, such as compounds 7, 9, 46, 59, 65, 74, and 86, are identified as non-teratogenic with anti-inflammatory and/or anti-angiogenic activity, expanding therapeutic options beyond existing thalidomide drugs.
Claims Coverage
The patent contains multiple independent claims focusing on thalidomide analogs, pharmaceutical compositions thereof, and methods of using these analogs to modulate TNF-α activity, angiogenesis, and inflammation. The following inventive features are extracted from the independent claims.
Thalidomide analogs defined by general formula I
The invention covers thalidomide analogs or their pharmaceutically acceptable salts characterized by a defined chemical structure according to general formula I, including specific definitions of substituents Y1, A, R1, R2, Z1, Z2, and ring B with detailed provisos and stereochemistry for the analogs.
Non-teratogenic activity of certain analogs
The thalidomide analogs are claimed to be non-teratogenic in embryonic assays such as zebrafish embryo and chicken embryo assays at concentrations within 10-200 μg/mL, overcoming a key limitation of prior thalidomide compounds.
Pharmaceutical compositions comprising thalidomide analogs
Pharmaceutical compositions are claimed that comprise thalidomide analogs or pharmaceutically acceptable salts thereof in combination with pharmaceutically acceptable carriers or excipients suitable for various administration routes.
Methods for inhibiting TNF-α activity, angiogenesis, and inflammation
Methods claim contacting cells or subjects with an effective or therapeutically effective amount of thalidomide analogs or pharmaceutical compositions to inhibit TNF-α activity and synthesis, angiogenesis, inflammation, or combinations thereof. Such methods include administering the compounds via multiple routes, optionally co-administered with other therapeutic agents such as anti-cancer, anti-angiogenic, or anti-inflammatory agents.
The patent claims cover structurally defined thalidomide analogs that are non-teratogenic, pharmaceutical compositions including them, and methods for modulating TNF-α activity, angiogenesis, and inflammation in vitro and in vivo. These claims focus on the dual therapeutic potential of the compounds with improved safety profiles compared to prior art.
Stated Advantages
Certain disclosed thalidomide analogs are non-teratogenic, providing improved safety over traditional thalidomide compounds.
The analogs possess anti-inflammatory and/or anti-angiogenic activities, enabling therapeutic use in diseases related to these pathways.
Some analogs are non-neurotoxic at therapeutically effective doses, potentially expanding utility in neurodegenerative and CNS diseases.
Pharmaceutical compositions containing these analogs can be administered by multiple routes, offering flexibility in treatment approaches.
Documented Applications
Treatment of disorders mediated by TNF-α activity, TNF-α protein levels, inflammation, and/or angiogenesis.
Use in treatment and inhibition of inflammatory disorders and autoimmune diseases such as rheumatoid arthritis, lupus nephritis, inflammatory bowel disease, multiple sclerosis, and others explicitly listed.
Treatment of neurodegenerative disorders associated with neuroinflammation, including Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, ALS, Huntington's disease, multiple sclerosis, cerebral amyloid angiopathy, tauopathies, macular degeneration, and others.
Inhibition of tumor angiogenesis and treatment of solid tumors, lymphomas, leukemias, multiple myeloma, and prevention of metastasis.
Treatment of pathological angiogenesis-related conditions, including ocular diseases like diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma, and skin diseases like psoriasis.
Use in reducing bleeding prior to surgery for resectable tumors.
Potential use in mitigating sarcopenia and muscle wasting conditions associated with elevated TNF-α.
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