Cholane Derivatives Modulating FXR and TGR5 Receptors
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Solution Overview
Problem
Current treatments for FXR and TGR5/GPBAR1 mediated diseases often result in severe side effects such as cholestatic pruritus, and existing compounds lack specificity and efficacy in modulating these receptors without inducing itching or causing liver injury.
Innovation Solution
Development of novel compounds, including BAR704, BARn704, BAR710, and BAR711, which act as selective or dual FXR and TGR5/GPBAR1 modulators, preventing or treating gastrointestinal, liver, cardiovascular, metabolic, and other disorders without inducing itching or liver damage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FXR agonists are used to treat FXR-mediated diseases, then therapeutic effects are achieved, but cholestatic pruritus occurs as a severe side effect
Solution Approach 1:
The patent uses TGR5/GPBAR1 as an intermediary target to achieve FXR-mediated therapeutic effects while avoiding direct FXR activation that causes pruritus. The cholane derivatives modulate TGR5/GPBAR1 signaling to produce anti-inflammatory and metabolic benefits without activating the pruritus pathway associated with direct FXR agonism.
Solution Approach 2:
The invention changes the molecular target parameter from direct FXR activation to TGR5/GPBAR1 modulation. By altering which receptor is primarily activated, the therapeutic profile is changed to maintain efficacy while eliminating the harmful side effect of cholestatic pruritus.
2Reliability
If existing bile acid derivatives are used to modulate FXR, then some therapeutic benefit is achieved, but lack of specificity and efficacy remains
Solution Approach 1:
The patent applies local quality by designing cholane derivatives with specific molecular modifications at particular positions (C6, C7, C24, C25) to achieve selective TGR5/GPBAR1 modulation. Each compound has specific stereochemistry and substitution patterns that confer selectivity for the desired receptor target while avoiding off-target effects.
Solution Approach 2:
The invention systematically varies molecular parameters including stereochemistry (6α vs 6β), substitution types (ethyl, hydroxyl, carboxyl), and position of modifications to optimize receptor selectivity and efficacy. This parameter optimization enables precise control over which receptor is activated and to what extent.
3Reliability
If existing compounds are used to treat liver diseases, then some therapeutic effects are achieved, but liver injury occurs as a side effect
Solution Approach 1:
The patent employs TGR5/GPBAR1 as an intermediary pathway to achieve liver protective effects without directly activating FXR in a manner that causes injury. The TGR5/GPBAR1-mediated signaling provides hepatoprotection through alternative mechanisms that do not lead to the toxic effects associated with conventional FXR agonists.
Data Source
AI summary
The present invention relates to compounds having cholane scaffolds of formula (I), said compounds for use in the treatment and/or prevention of FXR and TGR5/GPBAR1 mediated diseases.