Intestinally Targeted FXR Agonist Compounds to Limit Systemic Exposure
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Solution Overview
Problem
Current treatments for metabolic disorders, liver diseases, and gastrointestinal conditions associated with farnesoid X receptor (FXR) activity have limitations in efficacy and specificity, particularly in targeting FXR receptors in the intestines while minimizing systemic effects.
Innovation Solution
Development of compounds that act as FXR agonists, formulated for targeted delivery to the gastrointestinal tract, enhancing FXR receptor activation in the intestines while limiting systemic exposure, thereby treating conditions such as metabolic disorders, liver diseases, and intestinal inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FXR agonist compounds are administered systemically to treat metabolic disorders and liver diseases, then therapeutic efficacy is improved, but systemic side effects increase
Solution Approach 1:
The patent applies local quality by designing compounds with modified chemical structures (Formula I variants with specific R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 substituents) that enable selective accumulation in intestinal tissue. This structural modification creates compounds with different physicochemical properties that favor intestinal uptake and retention, thereby achieving local therapeutic action in the intestine while minimizing systemic distribution and associated side effects.
Solution Approach 2:
The patent employs intestinal uptake mechanisms as intermediaries to deliver FXR agonists selectively to intestinal tissue. By utilizing specific transport pathways and cellular uptake mechanisms that are predominant in intestinal epithelium, the compounds are preferentially delivered to the target site in the intestine, acting as an intermediary delivery system that reduces systemic exposure while maintaining therapeutic efficacy at the intestinal level.
2Adaptability or versatility
If conventional FXR agonists are used to treat gastrointestinal conditions, then therapeutic coverage is broad, but specificity for intestinal FXR receptors is reduced
Solution Approach 1:
The patent applies local quality by designing compounds with modified chemical structures (Formula I variants with specific R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 substituents) that enable selective accumulation in intestinal tissue. This structural modification creates compounds with different physicochemical properties that favor intestinal uptake and retention, thereby achieving local therapeutic action in the intestine while minimizing systemic distribution and associated side effects.
3Reliability
If high doses of FXR agonists are administered to enhance therapeutic effect, then metabolic disorder treatment efficacy is improved, but systemic exposure increases
Solution Approach 1:
The patent applies local quality by designing compounds with modified chemical structures (Formula I variants with specific R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 substituents) that enable selective accumulation in intestinal tissue. This structural modification creates compounds with different physicochemical properties that favor intestinal uptake and retention, thereby achieving local therapeutic action in the intestine while minimizing systemic distribution and associated side effects.
Data Source
AI summary
Described herein are compounds that are farnesoid X receptor agonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity.