FXR Agonists with Liver-Selective Tissue Distribution
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Solution Overview
Problem
There is a need for potent and efficacious Farnesoid X Receptor (FXR) agonists to treat liver disorders such as liver inflammation, fibrosis, and non-alcoholic steatohepatitis (NASH) that do not cause pruritus, a common adverse effect of existing FXR agonists.
Innovation Solution
Development of compounds of Formula (I) and their stereoisomers, tautomers, or pharmaceutically acceptable salts, which are administered to treat FXR-mediated diseases, including liver disorders, with a preference for liver tissue distribution to minimize skin-related adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FXR agonists are used to treat liver disorders, then therapeutic efficacy is achieved, but pruritus (skin-related adverse effect) occurs
Solution Approach 1:
The patent applies local quality by designing compounds with modified molecular structures (Formula I variations) that selectively enhance liver tissue affinity while reducing skin tissue interaction. This is achieved through specific structural modifications including different substituent groups (R1-R6), heterocyclic moieties, and stereochemical configurations that create localized molecular properties favoring liver targeting
Solution Approach 2:
The patent introduces tissue-selective intermediaries in the form of compounds containing specific functional groups and structural motifs that act as mediators between the FXR agonist activity and tissue distribution. These intermediaries include various heterocyclic structures, linker groups, and substituent patterns that modulate the compound's biodistribution to preferentially accumulate in liver tissue
2Reliability
If FXR agonists are administered to treat liver fibrosis and inflammation, then disease progression is slowed, but skin adverse effects increase
Solution Approach 1:
The patent modifies the molecular structure of FXR agonists to create local quality differences in tissue distribution. Specific structural features in Formula I (such as heterocyclic rings, substituent patterns, and stereochemistry) are designed to create molecular properties that favor liver tissue accumulation while minimizing skin tissue interaction, thereby maintaining therapeutic efficacy for liver fibrosis and inflammation while reducing skin adverse effects
3Object-affected harmful factors
If compounds are designed for preferential liver tissue distribution, then skin-related adverse effects are minimized, but compound structure complexity increases
Solution Approach 1:
The patent achieves tissue selectivity through localized structural modifications rather than complete molecular redesign. Specific regions of the molecule (such as heterocyclic moieties, substituent groups at specific positions, and stereochemical centers) are optimized for liver targeting while maintaining the core FXR agonist pharmacophore, thereby achieving selectivity with moderate structural complexity
Solution Approach 2:
The patent systematically varies molecular parameters including substituent types (halogens, alkyl groups, heterocycles), linker lengths, and stereochemical configurations to optimize liver tissue distribution. These parameter changes are made in a structured manner across multiple compounds of Formula I, allowing identification of optimal configurations that balance selectivity with structural simplicity
Data Source
AI summary
Disclosed herein are compounds that can be used as Farnesoid X Receptor (FXR) agonists, compositions containing these compounds and methods of use thereof.