TR Beta Agonist Scaffold Tuning for Selective NAFLD Therapy
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Solution Overview
Problem
Existing thyroid hormone receptor (TR) agonists used for treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are non-selective, leading to adverse effects on organs like the heart and bone, necessitating the development of more selective and specific agents that target TH signaling pathways.
Innovation Solution
Development of novel TR agonists with specific modifications, such as replacing the CN group on the azauracil ring with a hydrophobic group and altering the center phenyl ring substitution, maintaining TR beta efficacy while reducing TR alpha activity, thereby minimizing side effects and enhancing stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective TR agonists are used to treat NAFLD and NASH, then therapeutic efficacy is achieved, but adverse effects on heart and bone occur due to TR alpha activation
Solution Approach 1:
The patent applies local quality by modifying specific regions of the thyroid hormone analog molecule. The core structure retains TR beta binding capability while specific substituents (R1-R6) are engineered to provide selective interaction with TR beta over TR alpha, achieving organ-specific therapeutic action.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the thyroid hormone analog structure. Different substituents at positions R1-R6 alter the molecule's binding affinity and selectivity profile, enabling optimization of TR beta efficacy while minimizing TR alpha activation.
2Object-affected harmful factors
If TR agonists are designed to be highly selective for TR beta, then side effects are reduced, but development complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the thyroid hormone analog into distinct functional regions: a core structure essential for TR binding and substituent positions (R1-R6) that confer selectivity. This modular approach allows independent optimization of each region's properties.
Solution Approach 2:
The patent achieves universality by designing a core structure that maintains fundamental TR binding capability across variations, while substituent patterns provide specific selectivity functions. This allows the same core scaffold to serve multiple therapeutic purposes with different selectivity profiles.
Data Source
AI summary
Provided herein are novel thyroid hormone receptor (TR) agonists, e.g., having Formula I, II, or III. Also provided are methods of preparing the novel TR agonists and method of using the novel TR agonists for treating diseases or disorder modulated by TR agonists, such as NAFLD, NASH, diabetes, hyperlipidemia and/or hypercholesterolemia.