Intestinal FXR Agonists for Metabolic Disorder Treatment
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Solution Overview
Problem
There is a need for effective treatments for metabolic disorders, obesity, and inflammatory gastrointestinal conditions that do not require drastic lifestyle or dietary changes and can specifically target intestinal Farnesoid X receptor (FXR) to minimize side effects associated with systemic therapies.
Innovation Solution
Development of novel compounds that selectively target intestinal FXR, activating FXR receptors in the intestines to treat or prevent metabolic disorders, inflammation, cell proliferation diseases, and liver diseases, while minimizing systemic absorption to avoid side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic FXR agonists are administered to treat metabolic disorders, then beneficial effects are observed in chow-fed mice, but weight gain and glucose intolerance are exacerbated in diet-induced obesity mice
Solution Approach 1:
The patent applies local quality by developing compounds that selectively activate FXR receptors in the intestine rather than systemically throughout the body. This intestinal-specific activation achieves therapeutic benefits for metabolic disorders and inflammatory GI conditions while avoiding the harmful side effects of systemic FXR activation, such as exacerbated weight gain and glucose intolerance in diet-induced obesity models.
Solution Approach 2:
The invention segments the therapeutic effect by targeting a specific tissue (intestine) rather than the entire body. The compounds are designed to be absorbed in the gastrointestinal tract and activate FXR primarily in intestinal tissue, separating the beneficial local effects from the harmful systemic effects of FXR activation.
2Reliability
If known synthetic FXR ligands are used to treat metabolic disorders, then some therapeutic effects are achieved, but limited efficacy and exacerbated phenotypes occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of FXR ligands to alter their pharmacokinetic properties. The novel compounds have reduced systemic absorption while maintaining intestinal activity, changing the distribution parameter to achieve better therapeutic effectiveness and avoid the limited efficacy and exacerbated phenotypes seen with known synthetic ligands.
3Reliability
If FXR activation is used to treat metabolic syndrome, then glucose and lipid metabolism are regulated, but intestinal inflammation and other tissue side effects occur
Solution Approach 1:
The invention applies local quality by designing compounds that activate FXR selectively in the intestine where they are absorbed, rather than systemically throughout all tissues. This localized activation regulates metabolic functions through intestinal FXR while avoiding harmful side effects in other tissues such as liver, muscle, and adipose tissue.
Data Source
Figure 1A~1C
Figure 1D~1F
Figure 2A~2D
AI summary
Novel compounds having a formula 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.