FXR Agonist Compound Design for Efficacy and Safety Balance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for improved FXR agonists to modulate the Farnesoid X Receptor (FXR) for treating and preventing diseases and conditions.
Innovation Solution
Development of compounds that bind to the NR1H4 receptor (FXR) as agonists or modulators, represented by Formula (I), which are optionally substituted with specific functional groups and can form pharmaceutically acceptable salts, stereoisomers, or tautomers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional FXR agonists are used, then FXR modulation is achieved, but therapeutic efficacy and safety profile need improvement
Solution Approach 1:
The patent employs parameter changes by systematically modifying chemical structures of FXR agonists through varying substituents (R1-R6, Q, Z, L, Y', n) to optimize both therapeutic efficacy and safety profile. This involves changing physical and chemical parameters such as molecular weight, lipophilicity, and steric properties to achieve improved pharmacological characteristics while maintaining FXR binding affinity.
Solution Approach 2:
The invention creates composite molecular structures combining multiple functional groups and scaffolds (e.g., combining Q heterocyclic rings with substituted phenyl/pyridyl groups and various alkyl/cycloalkyl substituents) to achieve synergistic effects that improve both efficacy and safety compared to single-structure agonists.
2Reliability
If FXR agonist compounds are developed with specific functional groups, then binding affinity to NR1H4 receptor is improved, but molecular complexity increases
Solution Approach 1:
The patent segments the FXR agonist molecule into distinct functional domains: a core scaffold (Q), substituent regions (R1-R6), and optional moieties (Z, L, Y'). This segmentation allows systematic optimization of binding affinity in each region while managing overall molecular complexity through modular design principles.
Solution Approach 2:
The invention applies local quality by assigning specific functional groups to particular positions (R1-R6, Q, Z, L, Y') to enhance binding affinity at critical interaction points with the NR1H4 receptor, while keeping other regions simpler. This localized optimization allows improved binding without proportionally increasing overall molecular complexity.
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.