Selective THR-β Modulator Chemistry for Reduced Cardiac Side Effects
Solution Overview
Problem
Current treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are inadequate in halting disease progression and reversing fibrosis, which is a major predictor of liver disease evolution, and existing thyroid hormone receptor (THR) agonists lack selectivity, leading to cardiac side effects.
Innovation Solution
Development of novel THR-β modulators, including compounds of Formula I, which are agonists or antagonists of TRα and/or TRβ receptors, designed to treat liver-related disorders and other indications with improved selectivity, reducing cardiac side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing THR agonists are used to treat liver-related disorders, then therapeutic effect is achieved, but cardiac side effects occur due to lack of selectivity
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I with defined substituents R1-R11) that confer selective affinity for THR-β over THR-α. The structural features including specific ring systems, substituent positions, and molecular weight range (200-500 Da) are optimized to achieve liver-specific action while avoiding cardiac tissue effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as substituent types (halogen, alkyl, alkoxy groups at positions R1-R11), molecular weight (200-500 Da), and structural classes (aromatic, heterocyclic, bicyclic systems) to tune the compound's selectivity profile. These parameter optimizations enable differentiation between THR-β (liver) and THR-α (cardiac) receptor interactions.
2Reliability
If THR-β selectivity is improved to reduce cardiac side effects, then therapeutic index is enhanced, but compound design complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the molecular structure into distinct functional segments: a core aromatic or heterocyclic system (Formula I skeleton), substituent groups at specific positions (R1-R11 with defined chemical nature), and structural moieties (cyclic or acyclic components). This segmented approach allows systematic optimization of each segment's contribution to THR-β selectivity while managing overall molecular complexity.
Solution Approach 2:
The patent achieves universality by creating a versatile scaffold (Formula I) that can accommodate multiple substituent variations while maintaining core THR-β binding activity. The core structure serves multiple functions: providing structural rigidity, enabling diverse substituent attachment points, and maintaining molecular weight within the optimal range. This universal scaffold approach simplifies drug discovery by allowing exploration of multiple analogs from a single proven template.
Data Source
AI summary
Disclosed herein are compounds of Formula I:or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) CE is a moiety of Formula IV; iii) HD is a moiety of Formula V or VI; where the substituents are as defined herein. Disclosed are also pharmaceutical compositions comprising the above compounds, and methods of treating disease by administering or contact a patient with one or more of the above compounds.