Non-hormonal steroid modulators of NF-kB for treatment of disease
Inventors
McCall, John M. • Hoffman, Eric • Nagaraju, Kanneboyina
Assignees
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Publication Number
US-10857161-B2
Publication Date
2020-12-08
Expiration Date
Abstract
Provided herein is a pharmaceutical composition comprising a compound having the structural formula wherein the compound is present in an amount effective to treat or reduce the symptoms of muscular dystrophy. The therapeutically effective amount may be between 10 mg to 200 mg, or may be between 0.01 mg/kg to 10.0 mg/kg. Also provided are methods of treating or reducing the symptoms of muscular dystrophy, comprising the administration, to a patient in need thereof, of a therapeutically effective of the above compound.
Core Innovation
The disclosure describes non-hormonal steroid modulators of NF-kB for treating muscular dystrophy and other NF-kB-mediated diseases. It links muscle wasting pathology to TNF-alpha-driven, chronic NF-kB activation and proposes direct or indirect NF-kB modulation, including IKK inhibition. A broad structural Formula I scaffold is provided, with detailed definitions of substituents, stereochemical, tautomer, salt, and prodrug considerations.
The document also includes pharmaceutical compositions and therapeutically effective amount parameters for the compounds. The scaffold and related chemical descriptions support the generation of exemplified compounds, and chemical synthesis schemes are included for preparing exemplified compounds.
The disclosure further outlines NF-kB-mediated disease types in which the modulators are relevant, explicitly including multiple muscular dystrophies. It lists muscular dystrophy types such as Duchenne, Becker, limb girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss muscular dystrophy.
Claims Coverage
The independent claims cover three inventive aspects: an oral pharmaceutical composition in a suspension, and two methods of treating or reducing muscular dystrophy symptoms by administering the structurally defined compounds, with two different quantitative dosage ranges.
Oral suspension pharmaceutical composition of a structural formula compound
An oral pharmaceutical composition comprising a compound having the structural formula, comprising a therapeutically effective amount of the compound in a suspension.
Treating muscular dystrophy symptoms with a 10 mg to 200 mg dose
A method of treating or reducing the symptoms of muscular dystrophy, comprising administration to a patient in need thereof of a therapeutically effective amount of a compound having the structural formula, wherein the therapeutically effective amount is between 10 mg to 200 mg.
Treating muscular dystrophy symptoms with a 0.01 mg/kg to 10.0 mg/kg dose
A method of treating or reducing the symptoms of muscular dystrophy, comprising administration to a patient in need thereof of a therapeutically effective amount of a compound having the structural formula, wherein the therapeutically effective amount is between 0.01 mg/kg to 10.0 mg/kg.
Across the independent claims, the core coverage is limited to structurally defined compounds formulated as an oral suspension and administered for treating or reducing muscular dystrophy symptoms, with therapeutically effective amounts specified in mg (10–200 mg) or mg/kg (0.01–10.0 mg/kg).
Stated Advantages
Treating or reducing the symptoms of muscular dystrophy.
Documented Applications
NF-kB inhibition screening in C2C12 reporter cells responsive to TNF-alpha, with confirmation of NF-kB nuclear translocation by immunofluorescence.
In vivo efficacy evaluation in an mdx mouse model of dystrophy, including reported body weight and motor coordination/strength outcomes (rotarod) and muscle force metrics (EDL force contractions).
Assessment of glucocorticoid receptor binding using a glucocorticoid receptor binding assay with 3H-Dexamethasone, including a report of limited GR competitive binding for selected examples.
Treating or reducing muscular dystrophy symptoms.
NF-kB-mediated diseases.
Muscular dystrophy types explicitly listed include Duchenne, Becker, limb girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss muscular dystrophy.
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