Pyrazine FXR Agonist Composition for Oral NAFLD Treatment

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Solution Overview

Problem

Existing FXR agonists, such as isoxazole compounds, face challenges with low oral bioavailability, poor water solubility, and lower activation activity at the FXR target, limiting their effectiveness in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Innovation Solution

Development of pyrazine-based isoxazole compounds, including TM-01, TM-09, with specific structural modifications, which exhibit high permeability across cell membranes, strong agonistic activity on the farnesoid X nuclear receptor, and improved oral bioavailability, formulated into various pharmaceutical forms for treating NAFLD and NASH.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If isoxazole compounds are used as FXR agonists, then FXR activation activity is achieved, but oral bioavailability and water solubility are poor

Engineering Contradiction:

ImproveFXR activation activityVSAvoidoral bioavailability

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent modifies the chemical structure of isoxazole compounds by introducing pyrazine rings and various substituents (R1-R6 groups) to change physicochemical parameters such as water solubility and membrane permeability while maintaining FXR activation activity. This structural optimization resolves the contradiction between biological activity and pharmacokinetic properties.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures combining isoxazole cores with pyrazine rings and multiple functional groups to achieve a balance between FXR binding affinity and pharmacokinetic properties including oral bioavailability and water solubility.

Inventive Principle:

Principle #40Composite materials

2Reliability

If isoxazole compounds are used as FXR agonists, then FXR activation activity is achieved, but water solubility is poor

Engineering Contradiction:

ImproveFXR activation activityVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent introduces polar substituents and modifies molecular polarity through pyrazine ring incorporation to improve water solubility parameter while preserving the hydrophobic interactions necessary for FXR binding activity.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If existing FXR agonists are used, then some therapeutic effect is achieved, but activation activity at FXR target is lower

Engineering Contradiction:

Improvetherapeutic effectVSAvoidactivation activity at FXR target

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent optimizes specific local regions of the molecule (R1-R6 substituent positions) to enhance interaction with key residues in the FXR binding pocket, thereby improving activation activity at the target while maintaining overall therapeutic efficacy.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12486259B2FXR agonist having pyrazine structure, and preparation method and use

Publication Date: 2025.12.02 JIANGSU TASLY DIYI PHARMACEUTICAL CO LTD

AI summary

The present invention relates to a novel FXR agonist having a pyrazine structure, a preparation method therefor and the use thereof, and in particular relates to a compound as represented by the following general formula (I), or a hydrate, a solvate or a pharmaceutically acceptable salt thereof or a resolved single isomer thereof, which has the effect of treating non-alcoholic fatty liver disease.