FXR Agonist Compounds for Intestinal Selectivity and FGF19
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Solution Overview
Problem
Existing FXR agonists suffer from poor efficacy, metabolism issues, and adverse effects, particularly when used to treat liver diseases, and there is a need for compounds with improved potency, selectivity, and reduced detrimental effects.
Innovation Solution
Development of FXR agonists that demonstrate high cellular potency, preferential agonism in the gastrointestinal tract with minimal systemic effects, and reduced adverse reactions, formulated as pharmaceutical compositions for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FXR agonists are administered to treat liver diseases, then therapeutic benefits are achieved, but adverse effects and detrimental reactions occur
Solution Approach 1:
The patent applies local quality by designing compounds that exhibit preferential agonism in the gastrointestinal tract (specifically the ileum) with minimal systemic effects. This is achieved through structural modifications to FXR agonists that enhance intestinal selectivity, thereby producing therapeutic benefits in the target tissue while minimizing adverse effects in other organs.
Solution Approach 2:
The patent utilizes FGF19 as an intermediary mechanism. By activating FXR in the intestine, the compounds stimulate endogenous FGF19 secretion, which then mediates the therapeutic effects on bile acid synthesis and liver disease treatment. This indirect pathway through FGF19 reduces direct systemic FXR agonism and associated adverse effects.
2Productivity
If FXR agonists are administered to increase FGF19 secretion and reduce bile acid synthesis, then therapeutic effects are achieved, but systemic agonism and detrimental effects occur
Solution Approach 1:
The compounds are designed with enhanced intestinal selectivity, concentrating their agonist activity in the ileum where FXR activation stimulates FGF19 secretion. This local action at the intestinal level achieves the desired productivity (FGF19 secretion) while minimizing systemic agonism and associated harmful effects.
Solution Approach 2:
The patent segments the FXR agonist activity by tissue distribution, creating compounds that preferentially activate FXR in the gastrointestinal tract while having reduced activity in systemic tissues. This segmentation of pharmacological activity allows FGF19 secretion to be stimulated without widespread systemic agonism.
Data Source
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AI summary
The present disclosure relates generally to compounds that bind to FXR and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.