FXR Agonist Compound Design for Improved ADME and Lower Side Effects
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Solution Overview
Problem
Existing FXR agonists lack excellent physicochemical, in vitro and/or in vivo ADME properties and pharmacokinetics, and are associated with significant side effects.
Innovation Solution
Development of novel compounds with specific structural features, such as certain alkyl, cycloalkyl, aryl, and heteroaryl substitutions, through synthetic routes A, B, C, and D, to enhance ADME properties and reduce side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FXR agonists are used, then FXR-mediated therapeutic effects are achieved, but ADME properties and pharmacokinetics are poor and side effects are significant
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters including ring substitutions (fluoro, chloro, methoxy groups), chain lengths (C1-C6 alkyl groups), and structural configurations of the FXR agonist molecules. These parameter modifications optimize the balance between therapeutic efficacy and side effect profile while improving ADME properties
Solution Approach 2:
The patent employs composite molecular structures combining multiple functional groups (isoxazole rings, naphthalene cores, various substituents) to create FXR agonists with enhanced pharmacokinetic profiles. The composite nature of these molecules allows simultaneous optimization of solubility, stability, and receptor binding affinity
2Reliability
If existing FXR agonists are used, then FXR-mediated therapeutic effects are achieved, but ADME properties are poor
Solution Approach 1:
The patent systematically varies molecular parameters including hydrophobicity (through alkyl chain length), polarity (through heteroatom substitution), and molecular weight (through ring system modifications) to optimize ADME properties while maintaining therapeutic efficacy
3Ease of manufacture
If novel compounds with specific structural features are developed, then ADME properties and pharmacokinetics are improved, but structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the FXR agonist molecule into distinct functional modules: a core aromatic system (naphthalene or similar), intermediate linkers (ether or ester groups), and terminal functional groups (carboxylic acid, amide, or heterocyclic moieties). This modular approach allows systematic optimization of each segment for improved ADME properties
Solution Approach 2:
The patent implements local quality by introducing specific functional groups at strategic positions on the molecular scaffold. For example, fluorine or chlorine atoms are placed at specific ring positions to enhance metabolic stability, while alkyl chains of specific lengths are introduced to optimize membrane permeability without compromising overall solubility
Data Source
Figure 1~2
Figure 3~4
AI summary
Provided are a compound for modulating the activity of FXR having a structure of formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof.