Non-hormonal steroid modulators of NF-κβ for treatment of disease
Inventors
McCall, John M. • Hoffman, Eric • Nagaraju, Kanneboyina • Damsker, Jesse
Assignees
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Publication Number
US-11690853-B2
Publication Date
2023-07-04
Expiration Date
Abstract
The present invention relates to compounds and methods which may be useful as treatments of diseases.
Core Innovation
The invention relates to non-hormonal steroid compounds that modulate NF-baB signaling by targeting IbaB kinase (IKK) activity. The compounds include compounds having a generic structural Formula I with substituent definitions R1b1R9, and specific exemplary chemical structures, including named steroid-like compounds and derivatives.
The disclosure addresses NF-baB-mediated diseases and describes NF-baB activation via TNF-b1/IKKs leading to IbaB phosphorylation, degradation of IbaB, and nuclear NF-baB activity. The compounds are described as modulating NF-baB activity and are evaluated in C2C12 NF-baB luciferase reporter assays and related cellular assays, including confirmation of NF-baB nuclear translocation inhibition.
In vivo and phenotypic outcomes are described for representative examples, including improved cardiac function measures such as ejection fraction and fraction shortening. Additional readouts are reported in inflammation and disease-model contexts, including carrageenan paw edema, CAIA, OVA-induced acute allergic asthma, sickle cell disease model context, and an mdx heart failure model.
Claims Coverage
Two independent claims are identified. Both claims define a treatment method for muscular dystrophy using a compound or a salt with a therapeutically effective amount and require improvements in echocardiographic cardiac function measures, specifically ejection fraction and fraction shortening, with a threshold dose of at least 2 mg/kg/day. Each independent claim differs mainly in whether oral administration is expressly required and in the explicit inclusion of echocardiography as a measurement endpoint within the independent claim.
Treating muscular dystrophy by administering a therapeutically effective amount of a compound or a salt
A method of treating or reducing the symptoms of muscular dystrophy by administration, to the patient in need thereof, of a therapeutically effective amount of a compound for treating the muscular dystrophy, the compound having the structural formula or a salt thereof.
Dose threshold for muscular dystrophy treatment
The therapeutically effective amount is greater than or equal to 2 mg/kg/day.
Improving ejection fraction and fraction shortening in muscular dystrophy treatment
The method results in the patient having increased ejection fraction and fraction shortening as measured by echocardiography.
Oral administration of the compound for muscular dystrophy
The method comprises the oral administration, to a patient in need thereof, of a therapeutically effective amount of the compound or a salt thereof.
The claim set covers muscular dystrophy symptom reduction using structurally defined compounds or salts administered at a therapeutically effective amount of at least 2 mg/kg/day, with improved ejection fraction and fraction shortening as measured by echocardiography, and includes an independent pathway that expressly requires oral administration.
Stated Advantages
Improved echocardiographic ejection fraction and fraction shortening in a muscular dystrophy patient.
Modulates NF-baB signaling by targeting IbaB kinase (IKK) activity.
Provides compounds for NF-baB-mediated diseases, explicitly including muscular dystrophy.
Treating or reducing symptoms of muscular dystrophy.
Documented Applications
NF-baB modulator activity assessment using C2C12 NF-baB luciferase reporter assays, including cytotoxicity results and confirmation of NF-baB nuclear translocation inhibition.
In vivo evaluation in an mdx mouse model for muscular dystrophy-related heart failure readouts, with improved echocardiographic ejection fraction and fraction shortening.
In vivo evaluation in carrageenan paw edema, CAIA (collagen antibody induced arthritis), and OVA-induced acute allergic asthma contexts.
In vivo evaluation in a sickle cell disease model context.
NF-baB-mediated diseases, explicitly including muscular dystrophy.
Therapeutic use in a method of treating or reducing symptoms of muscular dystrophy in a patient, with outcomes characterized by increased ejection fraction and increased fraction shortening.
Echocardiography is used to measure improved ejection fraction and fraction shortening in the treated patient.
Cardiac functional outcomes associated with NF-baB signaling, as supported by ejection fraction and fraction shortening measures.
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