FXR Agonist Salt Composition for Solubility and Permeability
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Solution Overview
Problem
Existing FXR modulators face challenges with hydrophobicity, aqueous solubility, and membrane permeability, limiting their effectiveness in treating various diseases and conditions.
Innovation Solution
Development of tris(hydroxymethyl)aminomethane salts of specific compounds that act as FXR agonists, addressing improved physicochemical properties and enhancing membrane permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural ligands such as bile acids are used to activate FXR, then physiological functions are regulated, but the compounds have limited potency and specificity for therapeutic applications
Solution Approach 1:
The patent modifies the chemical structure of natural bile acid ligands by changing molecular parameters such as introducing fluorine atoms, modifying side chains, and adjusting core structures. This results in compounds with enhanced potency and specificity for FXR activation while maintaining the ability to regulate physiological functions like cholesterol metabolism and bile acid homeostasis.
Solution Approach 2:
The invention creates composite molecular structures that combine features of natural bile acids with synthetic pharmacological moieties. These composite compounds integrate the biological activity of natural ligands with the enhanced properties of synthetic structures, achieving both high potency/specificity and broad physiological regulation capabilities.
2Reliability
If existing FXR ligands are used to treat metabolic disorders, then cholesterol and bile acid metabolism are regulated, but the compounds lack sufficient selectivity to avoid off-target effects
Solution Approach 1:
The patent introduces specific functional groups and molecular features at particular positions in the FXR ligand structure. These local modifications create regions of high binding affinity and specificity for the FXR receptor, while the rest of the molecule maintains appropriate pharmacological properties. This localized optimization achieves high selectivity and minimizes off-target effects.
Solution Approach 2:
By systematically modifying molecular parameters such as introducing fluorine substitutions, altering side chain lengths, and adjusting core ring structures, the patent creates a series of compounds with progressively improved selectivity profiles. These parameter changes enhance binding specificity to FXR while reducing interactions with off-target receptors.
3Reliability
If high-potency FXR agonists are developed to improve therapeutic efficacy, then treatment effectiveness increases, but the complexity of synthesis and characterization increases
Solution Approach 1:
The patent divides the FXR ligand molecule into distinct functional segments: a core structure that provides binding affinity, side chains that confer specificity, and terminal groups that optimize pharmacological activity. This segmentation allows independent optimization of each region and simplifies the synthesis process by enabling modular assembly of components rather than requiring complex one-pot syntheses.
Solution Approach 2:
The invention employs preliminary structure-activity relationship (SAR) studies and computational modeling to identify optimal molecular features before undertaking full synthesis. This preliminary characterization guides the synthesis process, reducing the need for extensive trial-and-error experimentation and simplifying the overall development workflow.
Data Source
AI summary
The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The invention 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.