Small molecule AMPK activators
Inventors
Chen, Beibei • Mallampalli, Rama K. • Liu, Yuan
Assignees
United States Represented By Department Of Veterans Affairs Technology Transfer Program Iop9tt AS • University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11040935-B2
Publication Date
2021-06-22
Expiration Date
2037-10-04
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Abstract
Described herein are compounds that disrupt the interaction between Fbxo48 and phosphorylated-AMPK.
Core Innovation
The invention relates to compounds that disrupt the interaction between Fbxo48 and phosphorylated AMP-activated protein kinase (AMPK). AMPK is an enzyme that plays a critical role in cellular energy homeostasis by acting as a metabolic fuel gauge and master metabolic regulator. It exists as an obligate heterotrimer composed of catalytic kinase α subunit and regulatory β and γ subunits, and it is expressed in various tissues including liver, brain, and skeletal muscle.
Under metabolic stress, AMPK is activated through phosphorylation, notably at threonine 172 (Thr-172), leading to the suppression of anabolic processes and promotion of catabolic processes to restore energy balance. However, AMPK can be ubiquitinated and degraded, which blocks its phosphorylation and activation. Fbxo48 is identified as a protein that binds phosphorylated AMPK, targeting it for ubiquitination and degradation. The interaction between Fbxo48 and phosphorylated AMPK represents a regulatory mechanism affecting AMPK stability and activity.
The technical problem addressed by the invention is the need for compounds that prevent the ubiquitination and subsequent degradation of AMPK. By interfering with the Fbxo48 and phosphorylated AMPK interaction, the compounds aim to stabilize and activate AMPK. The invention provides chemical entities of Formula I and Formula II that bind to Fbxo48 and prevent its interaction with phosphorylated AMPK, thereby increasing phosphorylated AMPK levels and enhancing its protective metabolic effects. Such compounds have potential utility in treating various inflammatory and metabolic disorders.
Claims Coverage
The patent claims cover chemical compounds of specific structural formulas along with their stereoisomers and pharmaceutically acceptable salts or esters, methods of binding ubiquitin E3 ligase, and methods of treatment involving these compounds. The claims include a variety of substituted and unsubstituted alkyl, aryl, heterocyclic and heteroaryl groups defined in the formulas, as well as methods to disrupt Fbxo48 and phosphorylated-AMPK interaction.
Compounds of Formula I targeting Fbxo48 interaction with phosphorylated AMPK
The patent claims compounds of Formula I characterized by specific substituents including X groups (such as alkyl, —NH—CH2—, —O—CH2—), Z groups, R1 and R2 substituents that can form heterocyclic rings, and R3 groups that can be alkyl, carbocyclyl, aryl, or heteroaryl optionally substituted. These compounds disrupt the Fbxo48 and phosphorylated AMPK interaction to prevent AMPK degradation.
Compounds of Formula II with defined substituents targeting Fbxo48
The patent claims compounds of Formula II with specified X, Z, R1, R2, and R3 groups similar to Formula I but with R3 primarily being aryl or heteroaryl groups. The disclosed compounds include various substituted groups designed to bind Fbxo48 and prevent the interaction with phosphorylated AMPK, enhancing AMPK stability.
Methods to bind ubiquitin E3 ligase with the claimed compounds
The patent claims methods of binding ubiquitin E3 ligase by contacting it with compounds of Formula I or II or their stereoisomers or pharmaceutically acceptable salts or esters, thereby interfering with the ubiquitination of phosphorylated AMPK.
Therapeutic methods to treat inflammation and metabolic disorders
The claims encompass methods of treating inflammation, cytokine-driven inflammation, sepsis, acute lung injury, metabolic syndrome, and other inflammatory disorders by administering the compounds described herein. The methods further include increasing phosphorylated AMPK levels and disrupting the interaction between Fbxo48 and phosphorylated AMPK in cells or subjects.
The claims comprehensively cover novel chemical entities designed to interfere with the Fbxo48-phosphorylated AMPK pathway, their chemical variants, and methods of use for treating inflammation, sepsis, metabolic syndrome, and related disorders by enhancing AMPK activity and stability.
Stated Advantages
The compounds effectively prevent the degradation of AMPK by disrupting its interaction with Fbxo48, thereby increasing phosphorylated AMPK levels.
They show high potency in vitro and in vivo at low doses, well below predicted toxic doses.
They produce beneficial effects in multiple animal models of sepsis, pneumonia, and lung injury by reducing proinflammatory cytokines and lung damage.
The compounds enhance insulin sensitivity and improve metabolic parameters in obese mice models.
Documented Applications
Treatment of inflammation and cytokine-driven inflammatory disorders.
Treatment of sepsis and pneumonia.
Treatment of acute lung injury.
Treatment of metabolic syndrome.
Increasing levels of phosphorylated AMPK in subjects.
Disruption of the interaction between Fbxo48 and phosphorylated AMPK in cells or subjects to prevent AMPK degradation.
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