5HT1F receptor agonists and mitochondrial biogenesis
Inventors
LINDSEY, Christopher C. • Beeson, Craig C. • Peterson, Yuri Karl • Schnellmann, Rick G.
Assignees
MUSC Foundation for Research and Development • US Department of Veterans Affairs
Publication Number
US-11014892-B2
Publication Date
2021-05-25
Expiration Date
2037-11-02
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Abstract
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, promote mitochondrial biogenesis and are useful for the treatment of, for example, acute kidney injury and chronic kidney disease.
Core Innovation
The invention provides compounds of formula (I) and their pharmaceutically acceptable salts, which act as 5HT1F receptor agonists. These compounds promote mitochondrial biogenesis and are formulated into pharmaceutical compositions for therapeutic use.
The problem addressed by this invention is the lack of approved therapeutics for acute kidney injury (AKI) and the inadequacy of current treatments for chronic kidney disease (CKD). Both diseases are associated with mitochondrial dysfunction, and existing chemicals that induce mitochondrial biogenesis are limited.
The invention solves this problem by identifying novel 5HT1F receptor agonists that induce mitochondrial biogenesis, thereby enhancing the recovery of mitochondrial function in renal cells. The compounds have demonstrated utility in treating tubular and glomerular kidney diseases by stimulating mitochondrial biogenesis and improving renal function in both in vitro and in vivo models.
Claims Coverage
The patent contains one independent claim focusing on specific compounds, and claims directed to pharmaceutical compositions and therapeutic methods using these compounds. The main inventive features cover novel compounds with defined substituents, their use in treatment, and the induction of mitochondrial biogenesis.
Specific compounds as 5HT1F receptor agonists
The invention claims a set of compounds of formula (I) with defined substituents (L, R1, R2, R3, and R4) that act as selective 5HT1F receptor agonists, excluding 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide.
Pharmaceutical compositions containing the compounds
Pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula (I) or their pharmaceutically acceptable salts, combined with a pharmaceutically acceptable carrier.
Methods for treating kidney diseases
Methods of treating acute kidney injury or chronic kidney disease by administering a therapeutically effective amount of the compounds or their pharmaceutically acceptable salts, or the excluded compound, to patients in need thereof.
Method of inducing mitochondrial biogenesis
Methods for inducing mitochondrial biogenesis in a patient by administering a therapeutically effective amount of the compounds of formula (I) or the excluded compound, with a pharmaceutically acceptable carrier.
The independent claims cover novel 5HT1F receptor agonist compounds with defined chemical structures, their pharmaceutical formulations, and methods of therapeutic use for kidney diseases by promoting mitochondrial biogenesis.
Stated Advantages
The compounds promote mitochondrial biogenesis, leading to improved mitochondrial function in renal cells.
They provide a new therapeutic option for acute kidney injury and chronic kidney disease where current treatments are inadequate.
The invention includes compounds effective in both tubular and glomerular kidney cells, demonstrating broad renal therapeutic potential.
Documented Applications
Treatment of acute kidney injury.
Treatment of chronic kidney disease.
Induction of mitochondrial biogenesis as a therapeutic approach in patients.
Use in pharmaceutical compositions for administration via various routes including oral, parenteral, ocular, transdermal, and inhalation.
Application in therapeutic modulation of disorders linked to mitochondrial dysfunction in renal cells.
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