Intestine-Specific FXR Partial Agonists to Limit NASH Side Effects
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Solution Overview
Problem
Current FXR agonists for treating liver disorders like NASH are limited by undesirable side effects such as pruritus and adverse effects on serum lipid profiles, despite showing promising results, suggesting that intestine-specific activation may mitigate these issues.
Innovation Solution
Development of intestine-specific partial agonists of farnesoid X receptor (FXR), exemplified by compounds of Formula (I), which selectively target the intestine to elicit beneficial metabolic effects while minimizing systemic side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic FXR agonists are used to treat liver disorders, then therapeutic efficacy is improved, but side effects such as pruritus and adverse effects on serum lipid profiles occur
Solution Approach 1:
The invention divides the FXR activation effect into two segments: intestine-specific activation for therapeutic benefit and liver-specific activation for side effect prevention. This is achieved by designing a compound that selectively activates FXR in the intestine while avoiding FXR activation in the liver, thereby segmenting the therapeutic effect from the harmful effects.
Solution Approach 2:
The invention applies local quality by creating a compound with differential tissue selectivity - the compound exhibits high FXR binding affinity and activation capability in intestinal tissue, while showing minimal to no activation in liver tissue. This localized quality difference allows therapeutic action in the intestine without triggering liver-related side effects.
2Object-affected harmful factors
If intestine-specific FXR activation is achieved, then side effects are reduced, but the complexity of compound design increases
Solution Approach 1:
The invention changes the chemical structure parameters of FXR agonists to achieve intestine-specific selectivity. By modifying specific structural features of the compound (such as the pharmacophore elements and substituent groups), the compound's tissue distribution and receptor binding characteristics are altered to favor intestinal FXR activation while minimizing liver FXR activation.
Data Source
AI summary
An intestine-specific partial agonists of farnesoid X receptor (FXR) is disclosed, along with 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 FXR activity.