Substituted Resorcylic Acid AMPK Activators With Better Bioavailability
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Solution Overview
Problem
There is a lack of direct AMPK-activating drugs for treating metabolic disorders due to concerns about off-target effects and adverse side effects from synthetic activators, while natural compounds often indirectly activate AMPK through mitochondrial perturbations, leading to potential toxicity.
Innovation Solution
Development of substituted resorcylic acid compounds that directly bind to the allosteric site of AMPK, specifically activating the enzyme without causing mitochondrial perturbations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If resorcylic acid or its derivatives are used as AMPK activators, then metabolic disorders may be treated, but the compounds show poor water solubility and low bioavailability
Solution Approach 1:
The patent modifies the chemical structure of resorcylic acid compounds by introducing substituted groups at specific positions (such as methyl, hydroxyl, or halogen substituents on the aromatic ring). These structural parameter changes improve water solubility while maintaining AMPK activation activity, thereby resolving the contradiction between therapeutic effectiveness and solubility.
Solution Approach 2:
The invention creates composite chemical structures by combining resorcylic acid core with additional functional groups or moieties (such as sugar units, amino acids, or solubilizing groups). This composite approach enhances water solubility and bioavailability while preserving the pharmacological activity against metabolic disorders.
2Reliability
If resorcylic acid compounds are administered to improve insulin sensitivity, then glucose metabolism may be enhanced, but the compounds exhibit low bioavailability
Solution Approach 1:
The patent optimizes physical-chemical parameters of the compounds including molecular weight, logP value, and hydrogen bonding capacity by introducing specific substituents. These parameter modifications enhance oral bioavailability while maintaining the ability to improve insulin sensitivity and glucose metabolism.
Solution Approach 2:
The invention introduces intermediary functional groups or prodrug moieties that facilitate absorption and distribution. These intermediaries temporarily modify the compound to improve bioavailability, allowing the active resorcylic acid derivative to reach target tissues and exert its insulin-sensitizing effect.
3Reliability
If conventional AMPK activators like metformin are used, then type 2 diabetes may be treated, but they cause gastrointestinal side effects and lactic acidosis
Solution Approach 1:
The patent introduces specific substituted groups at particular positions on the resorcylic acid molecule to modulate local interactions with biological targets. This localized structural modification provides selective AMPK activation with reduced off-target effects, thereby treating diabetes while minimizing gastrointestinal side effects and lactic acidosis associated with metformin.
Solution Approach 2:
The invention transforms the potential harmful effects of conventional AMPK activators by using naturally occurring resorcylic acid derivatives that have a more favorable safety profile. The modified compounds activate AMPK through a different mechanism or with different kinetics, converting the harmful gastrointestinal effects into beneficial metabolic outcomes with improved tolerability.
Data Source
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AI summary
The present invention relates to a substituted resorcylic acid compound having general formula I and compositions comprising said compound for use in the activation of AMPK. The compounds are useful for the treatment or prevention of a condition, disorder or disease related to type 2 diabetes, non-alcoholic fatty liver disease and/or obesity.