THR Beta Agonist Compounds for Liver-Selective Thyroid Therapy
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Solution Overview
Problem
There is a need for thyroid hormone analogs that act as selective agonists for thyroid hormone receptor beta (THR beta) to treat disorders such as non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, and hypercholesterolemia, while avoiding the undesirable effects associated with THR alpha agonism and maintaining the beneficial effects of thyroid hormones.
Innovation Solution
Development of compounds that selectively agonize THR beta, including specific compounds of formula (I) and their pharmaceutically acceptable salts, which can be administered to patients to treat disorders mediated by THR beta.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If thyroid hormone analogs are used to treat disorders mediated by THR beta, then beneficial effects on liver disorders are achieved, but undesirable effects associated with THR alpha agonism occur
Solution Approach 1:
The patent applies segmentation by designing compounds that selectively target the THR beta receptor subtype while excluding THR alpha activation. The molecular structure is optimized to interact specifically with THR beta's binding pocket, dividing the therapeutic effect into organ-specific actions: liver benefits from THR beta agonism while cardiac side effects from THR alpha agonism are avoided.
Solution Approach 2:
The patent implements local quality by creating compounds with differential receptor subtype selectivity. The molecular structure incorporates specific substituents and structural features that confer preferential binding affinity for THR beta over THR alpha, enabling localized therapeutic effects in the liver without systemic cardiac side effects.
2Object-affected harmful factors
If selective THR beta agonists are developed, then side effects are reduced, but compound complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters such as substituent types, positions, and stereochemistry to optimize THR beta selectivity. The core structure undergoes controlled variations in physical-chemical parameters to enhance binding affinity for THR beta while maintaining appropriate pharmacokinetic properties for oral administration.
Data Source
AI summary
Provided herein are compounds of formula (I), or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, compositions of any of the foregoing, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by THR beta.