Selective Thyroid Hormone β-Receptor Agonists for Reduced Side Effects
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Solution Overview
Problem
Existing thyroid hormone-based treatments for conditions such as obesity, hyperlipidemia, and cardiovascular diseases face issues of low activity, poor permeability, and significant side effects like liver injury and cartilage damage, necessitating the development of novel thyroid hormone β receptor agonists with improved activity, selectivity, and safety.
Innovation Solution
A novel thyroid hormone β receptor agonist, represented by compounds of Formula I, is developed with specific structural modifications to enhance activity, selectivity, and safety, including variations in substituents like alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, and functional groups such as -COR10, -O-, -S-, and -SO2-, to target thyroid hormone receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing thyroid hormone-based treatments are used to treat obesity and metabolic diseases, then metabolic rate increases and weight loss occurs, but liver injury and cartilage damage occur as side effects
Solution Approach 1:
The patent applies local quality by designing the molecule to selectively activate thyroid hormone beta receptors in specific tissues (adipose tissue, liver, muscle) while avoiding receptors in sensitive tissues like cartilage and heart. This is achieved through structural modifications that confer tissue-selective agonist properties, allowing metabolic rate enhancement in target tissues without causing systemic side effects.
Solution Approach 2:
The invention segments the thyroid hormone receptor activation function by creating a selective agonist that acts only on TRβ1 and TRβ2 subtypes, separating the beneficial metabolic effects from the harmful side effects associated with non-selective thyroid hormone activation. This subtype-selective approach isolates the therapeutic action to specific physiological pathways.
2Reliability
If thyroid hormone analogues are developed to reduce side effects, then selectivity improves, but activity and permeability decrease
Solution Approach 1:
The patent employs parameter changes by systematically modifying molecular parameters including the core structure (pyridine, pyrimidine, triazine rings), substituent types (alkyl, aryl, heterocyclyl groups), and functional group positions to optimize the balance between selectivity and activity. These structural parameter adjustments enhance receptor binding affinity and tissue permeability while maintaining selective agonist properties.
Solution Approach 2:
The invention creates composite molecular structures combining heterocyclic cores with various substituent groups, forming complex molecules that integrate multiple functional elements. These composite structures achieve both high selectivity for TRβ receptors and improved pharmacokinetic properties including enhanced permeability and metabolic stability.
3Productivity
If high doses of thyroid hormones are administered to achieve therapeutic effects, then metabolic benefits increase, but side effects like heart problems and bone loss worsen
Solution Approach 1:
The patent introduces a selective TRβ agonist as an intermediary molecule that mediates the metabolic effects of thyroid hormone without requiring high doses. This intermediary compound activates specific metabolic pathways through TRβ receptor engagement, producing therapeutic benefits at low doses while avoiding the toxic effects associated with high-dose thyroid hormone administration.
Data Source
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AI summary
The present application provides novel thyroid hormone β receptor agonists with better activity, selectivity, or safety and are represented by Formula (I), and are used thereof to prevent, or treat diseases related to a β receptor agonist action. The disease include for example, obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver disease (fatty liver, NASH, NAFLD and the like), cardiovascular diseases (atherosclerosis and the like), thyroid diseases (hypothyroidism, thyroid cancer ,etc.