Bile Acid Receptor Modulators for Selective TGR5 Activation
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Solution Overview
Problem
Current modulators for the bile acid receptor TGR5 are weak and non-selective, failing to effectively activate TGR5 and inhibit FXR, which are crucial for regulating glucose homeostasis and insulin sensitivity in the context of obesity-associated type II diabetes.
Innovation Solution
Development of specific compounds and compositions that selectively activate TGR5 and inhibit FXR, including berberine derivatives and bile acid receptor modulators, which are designed to enhance energy expenditure and improve metabolic functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If endogenous bile acids are used to activate TGR5, then TGR5 activation occurs, but the potency and specificity are very weak
Solution Approach 1:
The patent modifies the chemical structure of bile acid ligands by changing parameters such as adding substituents at specific positions (e.g., 6α-substituted-3-oxo-5β-cholan-24-oic acid structures), varying chain lengths, and introducing different functional groups to enhance both potency and specificity for TGR5 activation while maintaining selective advantage over FXR
Solution Approach 2:
The invention introduces specific local modifications to the bile acid molecule structure, such as particular substituent groups at defined positions on the steroid nucleus, to create regions of enhanced interaction with TGR5 that provide selective activation while minimizing FXR activation
2Reliability
If bile acids are used to activate TGR5, then TGR5 activation occurs, but FXR activation also occurs simultaneously
Solution Approach 1:
The patent introduces specific local modifications to the bile acid structure (such as 6α-substitution patterns and specific side chain configurations) that create selective interaction with TGR5 while avoiding the structural features required for FXR activation, thereby achieving differential receptor activation
Solution Approach 2:
The invention changes key structural parameters of the bile acid ligand (including oxidation states at specific positions, substituent types and positions) to shift the activation profile toward selective TGR5 activation and reduced FXR activation, achieving therapeutic benefit with fewer side effects
3Reliability
If current TGR5 modulators are used, then some TGR5 activation occurs, but selectivity and enhanced efficacy are not achieved
Solution Approach 1:
The patent systematically varies structural parameters of the bile acid modulators including substituent types, positions, and configurations to optimize the balance between TGR5 activation potency and selectivity, achieving compounds that are both highly active and selectively targeted
Solution Approach 2:
The invention introduces specific local structural features (such as particular substituent groups at defined positions on the steroid nucleus) that serve as recognition elements for TGR5, enhancing selectivity by creating a molecular signature that preferentially binds TGR5 over other receptors
Data Source
AI summary
Disclosed herein, inter alia, compounds and methods of use thereof for the modulation of bile acid receptor activity.