Intestinal-Selective FXR Agonists for Metabolic Disorder Treatment
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Solution Overview
Problem
Current synthetic FXR ligands for treating metabolic and inflammatory gastrointestinal disorders have limited efficacy and can exacerbate phenotypes, particularly in diet-induced obesity models, and lack targeted action on intestinal FXR receptors.
Innovation Solution
Development of novel FXR agonists with specific structural formulas that are selectively absorbed in the intestines, activating intestinal FXR receptors to treat metabolic disorders, inflammation, and other gastrointestinal conditions without affecting the liver or kidney, and are designed to reduce weight gain, enhance insulin sensitivity, and improve glucose and lipid homeostasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known synthetic FXR ligands are administered to diet-induced obesity (DIO) mice, then FXR activation occurs, but weight gain and glucose intolerance are exacerbated
Solution Approach 1:
The patent applies local quality by designing compounds that selectively activate FXR receptors in the intestine while minimizing activation in the liver. This is achieved through structural modifications (Formula I compounds with specific R1-R16 substituents) that confer intestinal selectivity, thereby producing beneficial metabolic effects without the harmful systemic side effects observed with conventional FXR ligands
2Adaptability or versatility
If systemic FXR agonists are administered, then metabolic effects are observed in chow-fed mice, but harmful effects occur in diet-induced obesity models
Solution Approach 1:
The patent applies segmentation by dividing the FXR activation effect into tissue-specific components. The compounds selectively target intestinal FXR receptors while sparing hepatic FXR, thereby segmenting the therapeutic effect to achieve metabolic benefits without the harmful systemic effects that occur with pan-tissue FXR activation
3Reliability
If conventional FXR ligands are used, then broad FXR activation occurs, but targeted action on intestinal FXR is insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure parameters of FXR ligands (Formula I with specific R1-R16 groups) to alter tissue distribution and receptor selectivity. These structural parameter changes enable the compounds to achieve high intestinal selectivity while maintaining FXR activation capability, overcoming the limitation of conventional ligands that lack targeted action
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These FXR agonists effectively treat metabolic disorders, reduce weight gain, enhance insulin sensitivity, and improve glucose and lipid homeostasis by selectively activating intestinal FXR receptors, offering potent anti-obesity and glucose-lowering effects without systemic side effects.
Implementation Method 1
FXR agonists with formula (I) and pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof wherein the agonists are selectively absorbed in the intestines
Data Source
AI summary
Novel FXR agonists are disclosed, embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.