TGR5 Modulators Structural Optimization for Potency and Selectivity
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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 23-alkyl-substituted and 6,23-dialkyl-substituted derivatives of chenodeoxycholic acid, which act as TGR5 agonists or modulators to treat and prevent metabolic and inflammatory diseases by interacting with the TGR5 receptor.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TGR5 agonists are used, then some therapeutic effect is achieved, but potency and selectivity are insufficient for optimal treatment
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of bile acid derivatives, specifically at positions 6 and 23 of the steroid nucleus. By varying substituents (alkyl groups, halogens, hydroxyls) and their configurations, the invention optimizes both potency and selectivity for TGR5 receptor activation, resolving the contradiction between achieving therapeutic effect and improving measurement precision of receptor interaction.
2Reliability
If more potent and selective TGR5 modulators are developed, then therapeutic benefits are enhanced, but complexity of compound structure increases
Solution Approach 1:
The patent applies segmentation by dividing the TGR5 modulator development into systematic structural components: the core steroid nucleus, position 6 substituents, and position 23 substituents. This modular approach allows independent optimization of each segment to achieve potent and selective TGR5 modulation while maintaining a manageable structural framework based on known bile acid derivatives.
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 compounds effectively modulate the TGR5 receptor, providing therapeutic benefits in treating and preventing metabolic and inflammatory diseases by enhancing energy expenditure, reducing inflammation, and regulating bile acid and cholesterol homeostasis.
Implementation Method 1
compounds that modulate TGR5... interacting with the TGR5 receptor
Implementation Method 2
the cAMP-dependent induction of type 2 iodothyronine deiodinase (D2), which, by locally converting T4 into T3, gives rise to increased thyroid hormone activity
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.