Compounds for the treatment of acute and chronic kidney disease
Inventors
Suto, Mark J. • Mathew, Bini • Agarwal, Anupam • Traylor, Amie M.
Assignees
UAB Research Foundation • Southern Research Institute • US Department of Veterans Affairs
Publication Number
US-11753374-B2
Publication Date
2023-09-12
Expiration Date
2041-11-17
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Abstract
The present disclosure is concerned with biaryl aminomaleimide compounds for the treatment of disorders associated with heme oxygenase-1 (HO-1) signaling dysfunction such as, for example, kidney diseases (e.g., chronic kidney disease, acute kidney injury). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to biaryl aminomaleimide compounds and compositions useful for preventing and treating disorders associated with heme oxygenase-1 (HO-1) signaling dysfunction, including kidney diseases such as chronic kidney disease and acute kidney injury. The compounds have a specific chemical structure defined by variations in substituents R1a through R1e, R2, R3a through R3d, R4, and others, forming a biaryl aminomaleimide framework, or pharmaceutically acceptable salts thereof. These compounds can modulate HO-1 signaling and thereby address disorders linked to this pathway.
The background identifies acute kidney injury (AKI) as a major cause of morbidity and mortality in hospitalized patients, with high incidence and mortality rates in intensive care units. AKI is also linked to the development of chronic kidney disease (CKD). Despite advances in renal replacement therapy, no therapeutic intervention has proven successful, with general supportive care and dialysis remaining the primary treatments. There remains a need for new compounds and methods for treating kidney diseases associated with HO-1 signaling dysfunction.
Claims Coverage
The patent contains a primary independent claim directed to a compound with a defined chemical structure, and independent claims related to pharmaceutical compositions containing the compound, methods of treating HO-1 signaling dysfunction-associated disorders, methods of modifying HO-1 signaling in subjects and cells, identifying compounds that modulate HO-1 signaling, and kits comprising the compound with associated treatment components.
Compound structure with specified substituents
A compound having a biaryl aminomaleimide structure defined by substituents R1a-R1e, R2, R3a-R3d, R4, Cy1, R10, and R11, with specific selections for each substituent including hydrogen, halogen, alkyl groups, amino groups, cyano, hydroxy, and others, and conditions on substitutions and covalent bonding among substituents to form rings.
Pharmaceutical compositions comprising the compound
Pharmaceutical compositions comprising a therapeutically effective amount of the biaryl aminomaleimide compound or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers for administration.
Method of treating disorders associated with HO-1 signaling dysfunction
Methods for treating disorders related to HO-1 signaling dysfunction by administering an effective amount of the defined compound to a subject in need, with specificity to treat kidney diseases including chronic kidney disease and acute kidney injury.
Method of modifying HO-1 signaling in a subject
Methods of modifying (including increasing or activating) HO-1 signaling in a subject by administering an effective amount of the biaryl aminomaleimide compound, where the compound's activity is determined by assays involving vectors expressing HO-1 or its mutants.
Method of modifying HO-1 signaling in a cell
Methods of modifying HO-1 signaling in isolated cells by contacting the cell with an effective amount of the disclosed compound, where the cells can be mammalian or human and can be isolated prior to treatment.
Method of identifying compounds that modulate HO-1 signaling
A screening method involving contacting cells expressing a vector with promoter and enhancer elements linked to selectable markers with candidate compounds, determining marker expression, and identifying compounds that modulate HO-1 signaling accordingly.
Kits comprising the compound and treatment components
Kits including the biaryl aminomaleimide compound or its pharmaceutically acceptable salt with one or more of: an agent for treating HO-1 signaling dysfunction disorders, instructions for administering the compound, and instructions for treating such disorders.
The independent claims collectively cover the biaryl aminomaleimide compounds with defined substituent patterns, pharmaceutical compositions containing them, methods for treatment of disorders associated with HO-1 signaling dysfunction including kidney diseases, methods for modifying HO-1 signaling in subjects and cells, identification methods for HO-1 modulators, and kits for treatment including the compounds and relevant instructions or agents.
Stated Advantages
The compounds modulate heme oxygenase-1 signaling which is implicated in kidney diseases such as chronic kidney disease and acute kidney injury.
The compounds provide a new therapeutic option where current treatments for acute kidney injury and chronic kidney disease are limited and ineffective.
The compounds demonstrated ability to induce HO-1 expression and inhibit cisplatin-induced cytotoxicity in cell assays.
Documented Applications
Treatment of disorders associated with heme oxygenase-1 signaling dysfunction, specifically kidney diseases including chronic kidney disease and acute kidney injury.
Use in pharmaceutical compositions for prevention and treatment of kidney diseases related to HO-1 signaling dysfunction.
Methods for modifying HO-1 signaling in subjects or cells.
Use in kits containing the compounds and associated treatment agents or instructions.
Screening and identification of compounds that modulate HO-1 signaling.
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