2-Pyridone THRβ Agonist Crystal Forms for Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing thyroid hormone receptor agonists face challenges with reduced THRβ biological activity, THRβ/THRα selectivity, poor pharmacological stability, and poor pharmacokinetic effects, making it difficult to develop effective drugs for metabolic diseases.
Innovation Solution
A new 2-pyridone derivative with high agonist activity and selectivity on thyroid hormone β receptor, formulated in crystalline forms A, B, C, D, E, and F, exhibiting good stability, low hygroscopicity, and minimal heat influence, is developed for treating metabolic diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pyridazinone ring structural modifications are made based on MGL-3196, then some pharmacological activity is maintained, but THRβ biological activity and THRβ/THRα selectivity are reduced
Solution Approach 1:
The patent changes the fundamental structural parameters by replacing the pyridazinone ring with a pyridone ring, and further modifies the pyridone ring by replacing the nitrogen atom with a carbon atom. This series of parameter changes results in compounds that maintain pharmacological activity while improving THRβ/THRα selectivity and metabolic stability.
Solution Approach 2:
Instead of modifying the pyridazinone ring structure as done in prior art, the patent inverts the approach by completely changing the ring type to pyridone and then further inverting by replacing the nitrogen with carbon. This inversion strategy leads to improved selectivity and stability.
2Adaptability or versatility
If nitrogen atom on pyridone is replaced, then structural modification is achieved, but pharmacological activity is lost and stability becomes extremely poor
Solution Approach 1:
The patent carefully controls the parameter change by replacing the nitrogen atom with a carbon atom at specific positions (positions 1 or 2 of the pyridone ring) while maintaining the overall pyridone scaffold. This controlled parameter change achieves structural modification while preserving pharmacological activity and metabolic stability.
3Reliability
If crystalline forms with high stability are developed, then pharmacokinetic properties are improved, but manufacturing complexity increases
Solution Approach 1:
The patent changes the physical state parameter by developing multiple crystalline forms ( Forms 1-6) with different crystal structures. Each crystalline form has distinct X-ray powder diffraction patterns and thermal properties. This parameter change improves stability and pharmacokinetic properties while providing options for manufacturing.
Solution Approach 2:
The patent utilizes phase transitions by preparing multiple crystalline forms through different crystallization processes. The compounds can be transformed between different crystalline phases, and the patent provides specific crystallization conditions for obtaining each form, thereby improving stability without excessive manufacturing complexity.
Data Source
Figure 1
Figure 2~3
Figure 4
AI summary
The present disclosure belongs to the field of medicines. Disclosed in the present invention are a thyroid hormone β receptor agonist, a crystalline form, a preparation method and the use. The compound is a compound having a structural formula as represented by formula (I) or a pharmaceutically acceptable salt thereof. The X-ray powder diffraction pattern of a crystal form A of the compound of formula (I) comprises characteristic peaks at 6.10 ± 0.20°, 12.08 ±0.20° and 16.49±0.20° 2θ, as determined by means of using Cu-Ka radiation, The present invention develops a new 2-pyridone derivative. The compound has high agonistic activity and selectivity for the thyroid hormone β receptor, and can be used for treating metabolic diseases, particularly for treating diseases related to thyroid hormone receptor. The present invention also studies a series of crystal forms of the compound. The crystal form A compound has the advantages of good stability, low hygroscopicity, and small heat influence.