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-11939301-B2
Publication Date
2024-03-26
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 is directed to compounds of formula (I) which are 5HT1F receptor agonists that promote mitochondrial biogenesis (MB). These compounds and pharmaceutical compositions containing them are useful for the treatment of acute kidney injury (AKI) and chronic kidney disease (CKD). The compounds increase mitochondrial biogenesis, thereby improving mitochondrial function.
The problem being solved concerns the lack of approved therapeutics for treating acute kidney injury, with existing treatments for chronic kidney disease being inadequate. Kidney diseases are often associated with mitochondrial dysfunction, and current chemicals known to induce mitochondrial biogenesis are limited. Prior studies identified that 5HT1F receptor agonists promote mitochondrial biogenesis and aid recovery from renal injury, but new 5HT1F receptor agonists that induce mitochondrial biogenesis and are useful for treatment are needed.
Claims Coverage
The patent contains one independent claim which defines the chemical composition of compounds of formula (I). The main inventive features relate to the specific structural elements of these compounds, their substitution patterns, and their use in pharmaceutical compositions and methods for treating kidney diseases by inducing mitochondrial biogenesis.
Compound of formula (I)
A compound according to formula (I) featuring a variable linker L that can be a bond, —C(O)—, —C(O)CH2—, or —S(O)2—. The compound includes a substituent R1 selected from aryl, heteroaryl, or 8- to 10-membered bicyclic heteroaryl groups which may be mono-, bi-, or tri-substituted with groups including hydrogen, alkoxy, (═O), —NH-alkoxy, —NH2, —OH, halogen, lower alkyl, —NHC(O)N(CH3)2, —NHS(O)2-phenyl, or —NHC(O)-phenyl.
Variable R2 and R3 substituents on nitrogen atom
R2 and R3 independently can be hydrogen, lower alkyl, alkoxy, —NH-lower alkyl, heteroaryl, —S(O)2-phenyl, or indolinyl, with optional substitutions of lower alkyl, C(O)-alkoxy or —C(O)R4, or together with the nitrogen atom form a six-membered heterocycloalkyl optionally substituted with lower alkyl.
Definition of R4 substituent
R4 is defined as a heterocycloalkyl group optionally substituted with lower alkyl.
Exclusion of specific compound
The compounds exclude 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide.
Pharmaceutical compositions and methods
Pharmaceutical compositions comprising the compounds of formula (I) or their pharmaceutically acceptable salts, and methods of treating acute kidney injury and chronic kidney disease by administering therapeutically effective amounts of these compounds to induce mitochondrial biogenesis.
The claims cover novel compounds defined by formula (I) with specific substitution patterns on R1, R2, R3, and R4, along with pharmaceutical compositions containing these compounds, and therapeutic methods for kidney diseases involving mitochondrial biogenesis induction.
Stated Advantages
The compounds promote mitochondrial biogenesis.
Usefulness in treating acute kidney injury and chronic kidney disease.
Acceleration of recovery of renal function following injury.
Documented Applications
Treatment of acute kidney injury.
Treatment of chronic kidney disease.
Pharmaceutical use of the compounds to induce mitochondrial biogenesis.
Use in murine models for attenuating albuminuria in glomerular disease.
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