Small molecule AMPK activators
Inventors
Chen, Beibei • Mallampalli, Rama K. • Liu, Yuan
Assignees
United States Represented By Department Of Veterans Affairs Technology Transfer Program 10p9tt AS • University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11673853-B2
Publication Date
2023-06-13
Expiration Date
2037-10-04
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Described herein are compounds that disrupt the interaction between Fbxo48 and phosphorylated-AMPK.
Core Innovation
The invention provides compounds that disrupt the interaction between Fbxo48 and phosphorylated-AMPK. These compounds prevent the ubiquitination and subsequent degradation of AMP-activated protein kinase (AMPK), thereby increasing the levels of phosphorylated AMPK. The compounds are described by chemical formulas (Formula I and Formula II) featuring various substituents enabling specific binding and activity. They are capable of binding ubiquitin E3 ligases such as Fbxo48, inhibiting its effect on AMPK, and can be used as pharmaceutical agents for therapeutic purposes.
AMPK is a crucial enzyme for cellular energy homeostasis, acting as a metabolic fuel gauge and master metabolic regulator. It is activated under metabolic stress to restore energy balance by suppressing anabolic and promoting catabolic processes. In certain pathological conditions, such as cancer, AMPK is suppressed through ubiquitination and degradation by specific ubiquitin ligases like Fbxo48. This degradation disturbs energy homeostasis and contributes to diseases. The compounds described aim to block the targeted ubiquitination and degradation pathway to maintain AMPK activity.
The problem addressed is the lack of effective compounds that prevent the ubiquitination and degradation of AMPK mediated by Fbxo48. Existing treatments do not target this specific interaction, and disruption of AMPK function contributes to metabolic defects and inflammatory disorders. By stabilizing phospho-AMPK, the compounds aim to restore proper metabolic regulation and offer therapeutic benefits in inflammatory conditions, sepsis, pneumonia, acute lung injury, and metabolic syndrome.
Claims Coverage
The patent describes one independent claim focused on compounds of Formula II and their pharmaceutical compositions and methods of treatment.
Compounds of Formula II
Compounds characterized by a specific chemical structure defined as Formula II, wherein X is a C0-3 alkyl, aminoalkyl, or alkoxyalkyl linker; Z is a C1-2 alkyl or amino/oxy-containing group; R1 and R2 substituents are aryl or heterocyclic moieties, potentially forming a heterocyclic ring with the nitrogen atom; and R3 is an aryl or heteroaryl group optionally substituted with moieties selected from C═O, SO, SO2, or alkyl linkers with further substitutions (B groups) including alkyl, alkoxy, aryl, carbocyclyl, heterocyclyl, or heteroaryl.
Pharmaceutical composition comprising the compounds
Pharmaceutical compositions comprising the compounds of Formula II or their pharmaceutically acceptable salts, enabling therapeutic administration.
Methods of treatment using the compounds
Methods for treating inflammation, sepsis, and metabolic syndrome by administering therapeutically effective amounts of the compounds of Formula II or their pharmaceutically acceptable salts to a subject in need thereof.
Selection of specific compounds
A subgroup of compounds defined by selected substituents (for example, where B is haloalkyl, unsubstituted or substituted carbocyclyl or aryl) and specific examples disclosed within the claims.
The claims collectively cover novel compounds of Formula II with specific structural features, their pharmaceutical compositions, and therapeutic methods to treat inflammatory and metabolic disorders by modulating AMPK ubiquitination through interaction with Fbxo48.
Stated Advantages
The compounds effectively prevent ubiquitination and degradation of AMPK, thereby increasing phosphorylated AMPK levels.
They exhibit potent anti-inflammatory effects by inhibiting cytokine release, including IL-1β, IL-6, and TNF-α in in vivo models.
They show efficacy in treating inflammatory disorders such as sepsis, pneumonia, acute lung injury, and metabolic syndrome.
The compounds demonstrate bioactivity at low doses well below predicted toxic doses in animal models.
They improve metabolic parameters, including reducing body weight and fat mass, and enhance insulin sensitivity in obese mice models.
Documented Applications
Treatment of inflammation in subjects through administration of compounds that disrupt Fbxo48 and phosphorylated-AMPK interaction.
Treatment of cytokine-driven inflammation using the compounds to reduce proinflammatory cytokines.
Treatment of sepsis by reducing circulating proinflammatory cytokines and protecting against lung injury.
Treatment of pneumonia and acute lung injury by reducing lavage protein concentration, cell counts, bacterial load, and cytokine secretion.
Treatment of metabolic syndrome by improving insulin sensitivity, reducing fasting glucose, and reducing body weight and fat mass.
Methods to increase levels of phosphorylated AMPK in patients needing enhanced metabolic regulation.
Methods to disrupt the interaction between Fbxo48 and phosphorylated-AMPK in cells or subjects to promote AMPK stability and activity.
Interested in licensing this patent?