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-11623918-B2
Publication Date
2023-04-11
Expiration Date
2041-11-17
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Abstract
The present disclosure is concerned with thioquinolinone 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 thioquinolinone compounds for the treatment of disorders associated with heme oxygenase-1 (HO-1) signaling dysfunction, specifically kidney diseases such as chronic kidney disease and acute kidney injury. These compounds have specific structural formulas with defined substituents, aimed at modulating HO-1 signaling to prevent or treat such disorders.
The problem addressed is the high morbidity and mortality associated with acute kidney injury (AKI) and its linkage to chronic kidney disease (CKD). Current treatment options, including renal replacement therapy and dialysis, do not effectively reduce mortality rates, which remain as high as 80% in intensive care unit patients. There exists a need for effective compounds, compositions, and methods to treat kidney diseases connected with HO-1 signaling dysfunction.
The invention discloses specific compounds with defined chemical structures, pharmaceutical compositions comprising these compounds, and methods for treating disorders associated with HO-1 signaling dysfunction. Methods include administering effective amounts of the compounds to subjects or cells to modify or increase HO-1 signaling, thereby treating or preventing kidney diseases. Additionally, kits containing the compounds and therapeutic agents, along with instructions, are disclosed for managing disorders related to HO-1 signaling.
Claims Coverage
The patent includes a set of independent claims covering the compounds, pharmaceutical compositions, and methods of treating disorders through modulation of HO-1 signaling. The claims focus on chemical structures of compounds and their therapeutic uses.
Compounds having defined thioquinolinone structures
Discloses compounds represented by specific structural formulas where substituents R1a, R1b, R1c, R2a, R2b, and R3a through R3f are independently selected from hydrogen, halogen, CN, NH2, OH, NO2, various alkyl and alkoxy groups, and related groups, with conditions on the number and types of non-hydrogen substituents, and n being 1 or 2.
Pharmaceutical compositions comprising the disclosed compounds
Pharmaceutical compositions contain therapeutically effective amounts of the disclosed thioquinolinone compounds together with pharmaceutically acceptable carriers for administration.
Methods of treating disorders associated with HO-1 signaling dysfunction
Methods comprise administering an effective amount of the disclosed compounds to subjects in need, especially for treating kidney diseases such as chronic kidney disease or acute kidney injury.
Methods of modifying and increasing HO-1 signaling in a subject
Methods involve administering effective amounts of compounds to modify or activate HO-1 signaling, with identification of compounds that increase HO-1 by cell-based promoter assays.
The claims collectively cover the novel thioquinolinone compounds with defined substituents, their pharmaceutical formulations, and therapeutic methods for treating disorders associated with HO-1 signaling dysfunction, emphasizing kidney diseases and the modulation of HO-1 signaling pathways.
Stated Advantages
The compounds provide a new therapeutic option for treating kidney diseases associated with HO-1 signaling dysfunction where existing therapies have been unsuccessful.
The compounds can modulate HO-1 signaling, which is linked to protective effects in kidney diseases.
Pharmaceutical compositions and kits facilitate administration and use in clinical settings.
Documented Applications
Treatment of kidney diseases, including chronic kidney disease and acute kidney injury, associated with heme oxygenase-1 (HO-1) signaling dysfunction.
Modification of HO-1 signaling in subjects or isolated cells as therapy or for research.
Use in combination with agents such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers for treating disorders related to HO-1 signaling.
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