Crystalline FXR Agonist Form A for NASH Treatment
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Solution Overview
Problem
Current treatments for non-alcoholic steatohepatitis (NASH) lack effective pharmacological agents that can significantly reduce liver inflammation and improve hepatic steatosis and fibrosis.
Innovation Solution
A stable crystalline form (Form A) of a compound of formula (I), characterized by specific X-ray powder diffraction peaks, is developed. This compound acts as a FXR receptor agonist and is used in the manufacture of a medicament for treating NASH.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current pharmacological agents are used for NASH treatment, then some liver protection effect may be achieved, but they cannot significantly reduce liver inflammation and improve hepatic steatosis and fibrosis
Solution Approach 1:
The patent modifies the chemical structure parameters of FXR agonists by introducing specific substituents (R1-C1-3 alkyl group, R2-H or F) at positions 6 and 8 of the steroid nucleus, creating compound (I) with optimized pharmacological properties that significantly improve anti-inflammatory and anti-steatotic effects compared to existing agents
Solution Approach 2:
The patent introduces localized structural modifications at specific positions (6 and 8) of the FXR agonist molecule, where R1 represents C1-3 alkyl groups and R2 is H or F, creating localized structural features that enhance the compound's ability to reduce liver inflammation and improve hepatic function without affecting the entire molecular structure uniformly
2Stability of the object's composition
If amorphous or unstable solid forms of the compound are used, then formulation flexibility is maintained, but stability and hygroscopicity become problematic
Solution Approach 1:
The patent utilizes crystallization phase transition to convert the compound from amorphous or unstable solid forms to a stable crystalline form (Form A), characterized by specific X-ray powder diffraction peaks at 2θ angles of 12.72±0.2° and 25.27±0.2°, which significantly reduces hygroscopicity and improves storage stability
Solution Approach 2:
The patent selects common, easily removable solvents (alcohol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, water) for the crystallization process, which can be completely evaporated to leave the stable crystalline form, avoiding the need for expensive or difficult-to-remove solvents
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The crystal form A of the compound of formula (I) is stable, slightly hygroscopic, and effective in reducing NAS scores, improving inflammation, and enhancing hepatic function, with a certain dose-dependent effect on hepatic steatosis and fibrosis.
Implementation Method 1
FXR has a typical nuclear receptor structure, consisting of ligand-independent transcription activation domain, DNA binding domain, hinge region, and ligand binding region. FXR forms a heterodimer with retinoid X receptor (RXR), and binds with DNA to modulate gene transcription.
Implementation Method 2
the crystal form A of the compound of formula (I), which is characterized by X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles of 3.54±0.2°, 12.72±0.2°, and 25.27±0.2°.
Implementation Method 3
The crystal form A of the compound of formula (I) is stable, slightly hygroscopic, and effective in reducing NAS scores, improving inflammation, and enhancing hepatic function, with a certain dose-dependent effect on hepatic steatosis and fibrosis.
Data Source
AI summary
Disclosed are a solid form, a crystalline form, and crystal form A of a compound of formula (I) used as an FXR agonist, and a preparation method therefor. Also comprised is an application of the compound of formula (I) in preparation of a medication for treating nonalcoholic steatohepatitis (NASH).