TGR5 Modulators Bile Acid Derivatives Potency Selectivity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for more potent and selective TGR5 modulators to further understand the physiological and pharmacological actions of the TGR5 receptor, which is involved in various diseases such as obesity, diabetes, and inflammatory conditions, and to develop effective treatments.
Innovation Solution
Development of specific compounds, including 6α-ethyl-23(S)-methyl-chenodeoxycholic acid derivatives, that modulate TGR5 activity, which can be used in pharmaceutical compositions to treat or prevent metabolic, inflammatory, autoimmune, cardiac, kidney, gastrointestinal, and cancer diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TGR5 agonists are used, then TGR5 activation is achieved, but potency and selectivity are insufficient for effective treatment
Solution Approach 1:
The patent modifies the chemical structure of bile acid derivatives by introducing specific substituents at defined positions (e.g., R1-R6 groups, alkyl chains at C23 position) to optimize TGR5 binding affinity and selectivity, thereby enhancing therapeutic effectiveness while maintaining adequate potency
Solution Approach 2:
The invention creates composite molecular structures combining chenodeoxycholic acid core with various functional groups (oxadiazole, isoxazole, tetrazole rings, amino acid conjugates) to develop modulators with improved potency and selectivity profiles for TGR5 receptor
2Use of energy by moving object
If TGR5 agonists are administered, then energy expenditure is enhanced, but side effects and toxicity may occur
Solution Approach 1:
The patent introduces specific stereochemical configurations (23S vs 23R enantiomers) and localized substituent patterns at specific positions on the bile acid core to achieve selective activation of TGR5 receptor while minimizing off-target effects and toxicity
Solution Approach 2:
The invention develops prodrug forms and metabolites that provide transient TGR5 activation with controlled duration of action, allowing energy expenditure benefits while reducing cumulative toxicity and side effects through metabolite excretion
3Reliability
If more potent TGR5 modulators are developed, then disease treatment efficacy is improved, but complexity of compound structure increases
Solution Approach 1:
The patent divides the TGR5 modulator molecule into distinct functional segments: the bile acid core structure, the C23 substituent group, and additional functional groups at specific positions (R1-R6), allowing systematic optimization of each segment for efficacy while maintaining overall structural manageability
Solution Approach 2:
The invention creates a universal bile acid derivative scaffold that can accommodate multiple different substituent groups (oxadiazole, isoxazole, tetrazole, amino acid conjugates) to achieve multiple therapeutic effects including TGR5 activation, anti-inflammatory activity, and metabolic regulation from a single core structure
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These TGR5 modulators effectively treat or prevent diseases by activating or inhibiting the TGR5 receptor pathways, offering therapeutic benefits for a range of conditions by enhancing energy expenditure, regulating bile acid and cholesterol homeostasis, and influencing inflammatory responses.
Implementation Method 1
the cAMP-dependent induction of type 2 iodothyronine deiodinase (D2), which, by locally converting T4 into T3, gives rise to increased thyroid hormone activity
Implementation Method 2
Bile acids have been shown to induce internalization of the TGR5 fusion protein from the cell membrane to the cytoplasm
Data Source
AI summary
The application relates to compounds of formula A:or a salt, solvate, ester, tautomer, amino acide conjugate, or metabolite thereof. The compounds of formula A are TGR5 modulators useful for the treatment of various diseases, including metabolic disease, inflammatory disease, autoimmune disease, cardiac disease, kidney disease, cancer, and gastrointestinal disease.