23-Substituted Bile Acids as TGR5 Modulators
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Solution Overview
Problem
There is a need for effective modulators of the TGR5 receptor to treat and prevent various diseases such as central nervous system disorders, inflammatory diseases, and metabolic diseases like obesity and insulin sensitivity, as existing treatments are inadequate in addressing these conditions.
Innovation Solution
Development of specific compounds, including those of formula A and their pharmaceutically acceptable salts, solvates, or hydrates, that modulate the TGR5 receptor, which are administered to subjects to treat and prevent diseases by regulating bile acid and cholesterol homeostasis, fatty acid absorption, and protein and carbohydrate digestion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for central nervous system disorders, inflammatory diseases, and metabolic diseases, then current therapeutic approaches are maintained, but treatment effectiveness is inadequate
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of bile acid compounds through systematic variation of substituents at positions 23 and other locations on the cholane or ursane skeleton. This structural parameter modification creates a series of analogs with different biological activities, enabling the identification of compounds with optimized TGR5 modulatory effects for treating multiple disease types including central nervous system disorders, inflammatory diseases, and metabolic diseases
Solution Approach 2:
The patent achieves universality by developing bile acid compounds that can modulate the TGR5 receptor to address multiple disease conditions simultaneously. The disclosed compounds demonstrate broad therapeutic potential across different disease categories (central nervous system disorders, inflammatory diseases, metabolic diseases), allowing a single class of compounds to serve multiple therapeutic functions
2Reliability
If TGR5 modulators are developed to regulate bile acid and cholesterol homeostasis, fatty acid absorption, and protein and carbohydrate digestion, then metabolic control is improved, but compound specificity and selectivity must be maintained
Solution Approach 1:
The patent applies local quality by introducing specific substituents at particular positions on the bile acid skeleton, particularly at position 23 and other specific locations. This localized modification approach allows precise control over the compound's interaction with the TGR5 receptor while maintaining the overall molecular framework necessary for bile acid function, thereby achieving both metabolic regulation and compound specificity
Data Source
AI summary
The invention relates to compounds of Formula A: (A) or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The compounds of Formula A are TGR5 modulators useful for the treatment of various diseases, including obesity, insulin sensitivity, inflammation, cholestasis, and bile desaturation.