Non-hormonal steroid modulators of NF-κB for treatment of disease
Inventors
McCall, John M. • Hoffman, Eric • Nagaraju, Kanneboyina
Assignees
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Publication Number
US-10000525-B2
Publication Date
2018-06-19
Expiration Date
Abstract
The present invention relates to compounds and methods which may be useful as treatments of neuromuscular diseases such as muscular dystrophy, and as inhibitors of NF-κB for the treatment or prevention of muscular wasting disease, including muscular dystrophy.
Core Innovation
The invention relates to non-hormonal steroid NF-kB modulators and steroidal/cyclopenta[a]phenanthrene derivatives having defined stereochemistry and 2-hydroxyacetyl, acetate, oxo, ketone, and related ester or acetate forms. The compounds include specific 17-hydroxy steroid derivatives based on a cyclopenta[a]phenanthrene core, as well as Anecortave acetate and related acetate, hydroxyacetyl, oxo, and ketone structures.
The description connects NF-kB/I kappa B kinase signaling, including IKKalpha/IKKbeta, I kappa Bs, I kappa Bzeta, TNF-alpha, cachexia, muscle atrophy, proteolysis, and the ubiquitin-proteasome pathway, to the disclosed compounds. The compounds are positioned as indirect or direct NF-kB pathway modulators, including modulation involving phosphorylation of I kappa B and NF-kB signaling components.
The document also describes synthetic schemes and examples directed to generating these steroid-like derivatives and converting acetate intermediates to final hydroxyacetyl products. It includes preparative transformations, isolation, crystallization, chromatography, and reported yields in the examples.
Claims Coverage
The provided independent claims cover a pharmaceutical composition containing a selected compound group with a pharmaceutically acceptable carrier, and a method of reducing the symptoms of a broadly listed set of diseases by administering a therapeutically effective amount of a selected compound. Across the independent claims, the inventive features center on the defined therapeutic compound group in composition form and symptom-reducing administration across multiple named diseases.
Pharmaceutical composition with selected compound group and carrier
A pharmaceutical composition comprising a compound selected from the group consisting of the specified compounds together with a pharmaceutically acceptable carrier.
Method of reducing disease symptoms by administering selected compound group
A method of reducing the symptoms of a disease selected from the group consisting of the listed diseases by administering, to a patient in need thereof, a therapeutically effective amount of a compound selected from the group consisting of the specified compounds.
Compound selected from a group
A compound selected from the group consisting of the specified compounds.
Tablet or capsule dosage form
The pharmaceutical composition is formulated as a tablet or a capsule.
Combination with another therapeutic agent
The pharmaceutical composition includes another therapeutic agent.
The claim coverage centers on using a defined group of compounds in a pharmaceutically acceptable composition format and in an administration method intended to reduce symptoms across a long list of diseases, with dependent claims adding tablet or capsule dosage forms and optional inclusion of another therapeutic agent.
Stated Advantages
Inhibition of NF-kB signaling, including blockade of NF-kB nuclear translocation.
Lack of significant cytotoxicity in MTT assays.
Reported in vivo improvements in mdx mouse model outcomes including body weight, muscle mass, rota-rod motor coordination and strength, EDL force contraction measurements, and histology outcomes.
Minimal competitive binding in the glucocorticoid receptor binding assay for the tested compounds.
Reducing the symptoms of NF-kB-mediated diseases.
Documented Applications
NF-kB-mediated disorders and NF-kB activity modulation.
Treating NF-kB-mediated disorders by combination therapy.
Reducing the symptoms of the broadly listed disease set, including muscular dystrophy, arthritis, traumatic brain injury, spinal cord injury, sepsis, cancer, diabetes, glaucoma, retinal disease, asthma, chronic obstructive pulmonary disease, lupus, inflammatory bowel disease, AIDS, HIV-1, Parkinson's disease, multiple sclerosis, Alzheimer's disease, amyotropic lateral sclerosis, Huntington's disease, cataracts, hearing loss, and Sjogren's syndrome.
NF-kB inhibition in C2C12 skeletal muscle cells using an NF-kB luciferase reporter with TNF-alpha stimulation.
Use in an mdx mouse model of dystrophy, with outcomes including body weight, gastrocnemius muscle mass, rota-rod motor coordination and strength, EDL force contraction measurements, and histology.
Assessment of glucocorticoid receptor binding via a dexamethasone competitive binding assay.
Treating NF-kB-mediated muscular wasting, including muscular dystrophy such as Duchenne and Becker muscular dystrophy.
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