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-10206933-B2
Publication Date
2019-02-19
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 compounds and steroid-like triterpenoid or cyclopenta[a]phenanthrene derivatives that modulate NF-κB, including inhibition of IKKs and related pathway steps, for treatment and/or prevention of NF-κB-mediated diseases. The disclosure is directed to reducing symptoms of a disease in a patient in need thereof by administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier together with a compound having a steroid structure or a compound having a defined structure, or a salt thereof.
The background and evaluation context link chronic NF-κB activation with catabolic processes that contribute to muscle wasting, and the disclosure highlights muscular wasting disorders such as Duchenne muscular dystrophy and Becker muscular dystrophy. The described NF-κB pathway context includes tumor necrosis factor-alpha (TNF-α), IκB kinases (IKKs), and downstream signaling components such as p65/RelA and NEMO (NF-κB essential modulator).
A generic steroid structure is provided as Formula I, with variable substituents R1–R9, along with detailed definitions and constraints for the substituents, including optional double-bond cases and exclusions on R9. The document further describes steroid-like triterpenoid or cyclopenta[a]phenanthrene derivatives having specific substitution patterns, including 17-hydroxy and 2-hydroxyacetyl groups, related acetate derivatives and stereochemical variants, and multiple synthetic schemes and preparation examples for compounds within these structural classes [procedural detail omitted for safety].
Claims Coverage
The independent claims cover one inventive feature: a method of reducing symptoms of selected NF-κB-associated diseases through administration of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound with a specified steroid structure, or a salt thereof. Dependent claims further refine the disease selection and optionally constrain the pharmaceutical composition to tablet or capsule dosage forms.
Reducing symptoms of selected NF-κB-associated diseases by administering steroid compound composition
A method for reducing the symptoms of a disease selected from atherosclerosis, hypercholesterolemia, chronic heart failure, ischemia/reperfusion, angina pectoris, and myocarditis by administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier together with a compound having the structure and/or a salt thereof.
Treating atherosclerosis
The method wherein the disease selected for symptom reduction is atherosclerosis, using the administration framework of the pharmaceutical composition comprising the pharmaceutically acceptable carrier and the compound having the structure and/or a salt thereof.
Treating hypercholesterolemia
The method wherein the disease selected for symptom reduction is hypercholesterolemia, using the administration framework of the pharmaceutical composition comprising the pharmaceutically acceptable carrier and the compound having the structure and/or a salt thereof.
Treating chronic heart failure
The method wherein the disease selected for symptom reduction is chronic heart failure, using the administration framework of the pharmaceutical composition comprising the pharmaceutically acceptable carrier and the compound having the structure and/or a salt thereof.
Tablet or capsule pharmaceutical composition form
The method wherein the pharmaceutical composition is formulated as a tablet or a capsule.
Overall claim coverage centers on administering a pharmaceutically acceptable-carrier pharmaceutical composition containing a steroid compound, or salt, having a specified structure to reduce symptoms of a selected disease from a defined set, with dependent claims further narrowing the disease selection and, in some cases, limiting the pharmaceutical composition to tablet or capsule dosage forms.
Stated Advantages
Reducing the symptoms of an NF-κB-mediated disease selected from the listed diseases.
The compounds generally show no significant glucocorticoid receptor competitive binding.
Documented Applications
Treatment and/or prevention of NF-κB-mediated diseases, including muscular wasting disorders such as Duchenne muscular dystrophy and Becker muscular dystrophy.
Reducing symptoms of diseases selected from atherosclerosis, hypercholesterolemia, chronic heart failure, ischemia/reperfusion, angina pectoris, and myocarditis.
Evaluation as NF-κB modulators using a C2C12 NF-κB luciferase reporter assay.
Assessment of NF-κB nuclear translocation by immunofluorescence.
Testing in an mdx mouse model of dystrophy, including functional tests and histology [procedural detail omitted for safety].
Glucocorticoid receptor binding assessment using a glucocorticoid receptor binding assay with 3H-dexamethasone and reporting generally no significant GR competitive binding.
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