Selective THR Beta Agonist Compounds for Limiting THR Alpha Effects
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Solution Overview
Problem
There is a need for thyroid hormone analogs that act as selective agonists for THR beta to treat conditions like 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, specifically formulated as pharmaceutical compositions, which can be administered to patients to treat disorders mediated by THR beta, such as non-alcoholic steatohepatitis (NASH).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If thyroid hormone analogs are used to treat disorders mediated by THR beta, then therapeutic benefits are achieved, but undesirable effects associated with THR alpha agonism occur
Solution Approach 1:
The invention segments the thyroid hormone receptor system into two distinct isoforms (THR alpha and THR beta) and develops compounds that selectively target only the THR beta isoform. This segmentation allows the drug to achieve therapeutic benefits through THR beta agonism while avoiding the harmful effects associated with THR alpha activation, thereby resolving the technical contradiction between efficacy and safety
Solution Approach 2:
The patent applies local quality by creating compounds with specific molecular structures (formula I and formula II) that exhibit selective affinity for THR beta receptors in particular tissues (liver, adipose tissue) while having minimal affinity for THR alpha receptors in other tissues (heart, bone). This localized selectivity enables therapeutic action at target sites without causing systemic side effects
2Reliability
If THR alpha agonism is activated to treat disorders, then certain therapeutic effects are achieved, but serious side effects occur including tachycardia, hypertrophism, and decreased bone mineral density
Solution Approach 1:
The invention extracts the harmful THR alpha agonism component from the therapeutic mechanism by designing compounds that exclusively or preferentially activate THR beta receptors. The compounds of formula I and formula II are structurally optimized to bind THR beta with high affinity while having negligible affinity for THR alpha, thereby extracting the beneficial metabolic effects without the harmful cardiac and skeletal side effects
Solution Approach 2:
The patent converts the previously harmful non-selective thyroid hormone agonism into a beneficial selective THR beta agonism. By inverting the selectivity profile to favor THR beta over THR alpha, the invention transforms the historical problem of side effects into a solution where the same hormonal pathway is activated but in a tissue-specific manner that produces only beneficial outcomes
Data Source
AI summary
Provided herein are compounds, preferably thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by THR beta.