Nitrogen Tricyclic FXR Modulators for Metabolic Disease Treatment
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Solution Overview
Problem
Current FXR modulators have limitations in effectively treating a wide range of diseases mediated by the Farnesoid X Receptor (FXR), including dyslipidemia, obesity, and liver-related disorders, with a need for compounds that offer improved biological activity and pharmacokinetic advantages.
Innovation Solution
Development of nitrogen-containing tricyclic compounds that bind to FXR, acting as modulators to regulate its activity, and their pharmaceutical compositions for use in treating diseases such as non-alcoholic fatty liver disease, atherosclerosis, and other metabolic disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FXR modulators are used, then some disease treatment effects are achieved, but the biological activity and pharmacokinetic profiles are insufficient for effectively treating a wide range of FXR-mediated diseases
Solution Approach 1:
The patent applies parameter changes by systematically varying key structural parameters of the FXR modulator molecules, including introducing nitrogen-containing tricyclic core structures, modifying substituent groups at specific positions (R1-R6), and adjusting molecular weight and lipophilicity parameters to optimize both biological activity and pharmacokinetic properties for broad disease treatment
Solution Approach 2:
The invention employs composite molecular structures combining nitrogen-containing heterocyclic rings with tricyclic frameworks and various functional substituents, creating composite modulator molecules that simultaneously achieve high binding affinity to FXR and improved pharmacokinetic profiles across multiple disease indications
2Ease of manufacture
If compound structure is simplified for ease of manufacture, then manufacturing becomes easier, but biological activity and FXR binding affinity may be reduced
Solution Approach 1:
The patent applies segmentation by dividing the complex FXR modulator molecule into distinct synthetic modules: a core nitrogen-containing tricyclic structure, intermediate linking groups, and terminal functional substituents. This modular segmentation enables stepwise synthesis while maintaining the essential pharmacophore features required for FXR binding affinity
Solution Approach 2:
The invention uses versatile intermediate compounds containing reactive functional groups (halogens, boronic acids, boron esters) that serve as intermediaries in cross-coupling reactions. These intermediaries facilitate the assembly of complex modulator structures from simpler building blocks, balancing manufacturing ease with preservation of binding affinity
Data Source
AI summary
A nitrogen-containing tricyclic compound which acts as modulator of FXR, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and the use of the compound for the treatment of disease and/or condition mediated by FXR are described. And a pharmaceutical composition containing the compound disclosed herein and a method of treatment of disease and/or condition mediated by FXR comprising administering the compound or the pharmaceutical composition thereof are also described.