NR1H4 FXR Agonist Compounds for Broad Disease Modulation
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Solution Overview
Problem
There is a need for improved FXR agonists that can effectively modulate the Farnesoid X Receptor (FXR) to treat a wide range of diseases and conditions, including chronic intrahepatic and extrahepatic cholestatic conditions, liver fibrosis, inflammatory bowel diseases, metabolic disorders, and various forms of cancer, as existing FXR agonists are inadequate in addressing these complex physiological processes.
Innovation Solution
Development of novel compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators, specifically designed to target and activate FXR, thereby regulating bile acid metabolism, reducing inflammation, and modulating gene expression to treat conditions such as cholestatic disorders, liver diseases, metabolic disorders, and cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FXR agonists are used, then some FXR modulation activity is achieved, but they are inadequate in addressing complex physiological processes and treating a wide range of diseases
Solution Approach 1:
The patent employs parameter changes by systematically varying molecular structures of FXR agonists, including modifications to the core scaffold, substituent groups, and molecular properties to optimize binding affinity and selectivity. This allows the development of compounds with enhanced FXR modulation effectiveness while maintaining the ability to address diverse disease conditions through tailored molecular design
2Adaptability or versatility
If novel FXR agonist compounds are developed with improved disease treatment coverage, then versatility in treating multiple conditions is enhanced, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the FXR agonist molecules into distinct functional modules or pharmacophoric elements that can be independently optimized. This modular approach allows for systematic exploration of structure-activity relationships while managing molecular complexity through organized design principles
Solution Approach 2:
The patent develops FXR agonist compounds with universal applicability across multiple disease indications by designing molecules that maintain core FXR binding capabilities while allowing for indication-specific optimization. This multi-functional design enables a single compound or small series of compounds to address diverse pathological conditions through FXR modulation
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
The compounds effectively activate FXR, leading to improved bile flow, hepatoprotection, anti-fibrotic effects, and regulation of insulin sensitivity, thereby providing therapeutic benefits in treating chronic liver diseases, metabolic disorders, and cancer, including reducing serum triglycerides, cholesterol levels, and preventing gallstone formation.
Implementation Method 1
compounds which bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR
Data Source
AI summary
The present disclosure relates generally to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.