Bile Acid Derivatives as Dual FXR TGR5 Agonists
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Solution Overview
Problem
There is a need for the development of FXR and/or TGR5 modulators for the treatment and prevention of various diseases, including metabolic, inflammatory, and liver diseases, as existing modulators are not sufficient in addressing these conditions effectively.
Innovation Solution
The development of compounds represented by Formula (I) and their pharmaceutical compositions, which act as FXR and/or TGR5 modulators, are administered to treat and prevent diseases by modulating these receptors, thereby addressing the need for effective treatment options.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FXR and TGR5 modulators are used, then some therapeutic effect is achieved, but they are not sufficient in effectively treating metabolic, inflammatory, and liver diseases
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of bile acid derivatives, specifically at positions 6, 7, and 12 of the steroid nucleus, and by varying the substituent groups (R1-R6) to optimize the balance between therapeutic effectiveness and disease coverage. This structural parameter optimization enables the compounds to effectively target both FXR and TGR5 receptors across multiple disease types.
Solution Approach 2:
The patent employs composite material principles by designing compounds that combine multiple functional groups and structural features within a single molecule. The bile acid derivatives incorporate hydroxyl groups, substituent groups, and specific stereochemical configurations that collectively enable dual receptor modulation (FXR and TGR5), creating a composite therapeutic agent with enhanced versatility for treating metabolic, inflammatory, and liver diseases.
2Adaptability or versatility
If new compounds are developed to address multiple diseases, then disease coverage is improved, but the complexity of compound development increases
Solution Approach 1:
The patent applies universality by designing bile acid derivatives that can simultaneously modulate both FXR and TGR5 receptors through a single compound structure. This multi-functionality is achieved by incorporating specific structural features (hydroxyl groups at positions 3α and 7α, and appropriate substituent groups) that enable the compound to interact with multiple target receptors, thereby covering metabolic, inflammatory, and liver diseases without requiring separate compounds for each disease type.
Solution Approach 2:
The patent manages structural complexity through systematic parameter changes, where specific positions (R1-R6) are independently optimized to achieve the desired dual receptor activity. This modular approach to structure-activity relationship optimization allows for controlled complexity, where each substituent group serves a specific function in binding to either FXR or TGR5, rather than requiring entirely complex and unrelated molecular structures.
Data Source
AI summary
The present invention provides compounds of Formula I:pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR and/or TGR5.