TRβ-Selective Thyromimetics for Remyelination Without Cardiotoxicity

Solution Overview

Problem

Developing selective thyromimetics has been challenging due to the high sequence homology of thyroid hormone receptor subtypes, and existing thyromimetic compounds face limitations in therapeutic windows and side effects such as cardiotoxicity and bone demineralization, while there is a need for compounds that can effectively treat neurodegenerative disorders and fibrotic diseases.

Innovation Solution

The development of thyromimetic compounds represented by Formulae I, II, III, IV, V, VI, VII, and VIII, which are designed to selectively target thyroid hormone receptors, providing therapeutic benefits for neurodegenerative disorders like multiple sclerosis and fibrotic diseases by modulating TGF-β signaling.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If thyroid hormone (TH) is used as therapy to stimulate remyelination, then remyelination is improved, but cardiotoxicity and bone demineralization occur

Engineering Contradiction:

Improveremyelination efficacyVSAvoidcardiotoxicity and bone demineralization

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by developing TRβ-selective thyromimetics that target specific tissue distributions. TRβ is enriched in the liver, while TRα is enriched in the heart and bone. By selecting for TRβ activity, the compound achieves remyelination stimulation without activating the harmful pathways in heart and bone associated with TRα activation, thus resolving the contradiction between remyelination efficacy and cardiotoxicity/bone demineralization

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the molecular parameter of thyroid hormone receptor selectivity by designing compounds with specific molecular structures (Formulae I-VIII) that preferentially bind TRβ over TRα. This parameter change in receptor selectivity allows the therapeutic to achieve remyelination benefits while avoiding the harmful effects of non-selective TH therapy

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If non-selective thyromimetics are used to treat neurodegenerative disorders, then therapeutic coverage is improved, but side effects increase

Engineering Contradiction:

Improvetherapeutic coverageVSAvoidside effects

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by developing TRβ-selective thyromimetics that target specific tissue distributions. TRβ is enriched in the liver, while TRα is enriched in the heart and bone. By selecting for TRβ activity, the compound achieves remyelination stimulation without activating the harmful pathways in heart and bone associated with TRα activation, thus resolving the contradiction between remyelination efficacy and cardiotoxicity/bone demineralization

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the molecular parameter of thyroid hormone receptor selectivity by designing compounds with specific molecular structures (Formulae I-VIII) that preferentially bind TRβ over TRα. This parameter change in receptor selectivity allows the therapeutic to achieve remyelination benefits while avoiding the harmful effects of non-selective TH therapy

Inventive Principle:

Principle #35Parameter changes

3Reliability

If existing thyromimetic compounds are used, then some therapeutic effects are achieved, but therapeutic window is limited

Engineering Contradiction:

Improvetherapeutic effectsVSAvoidtherapeutic window

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent changes the molecular parameter of thyroid hormone receptor selectivity by designing compounds with specific molecular structures (Formulae I-VIII) that preferentially bind TRβ over TRα. This parameter change in receptor selectivity allows the therapeutic to achieve remyelination benefits while avoiding the harmful effects of non-selective TH therapy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by combining multiple structural features in the thyromimetic compounds (Formulae I-VIII) to achieve optimal TRβ selectivity and therapeutic efficacy. The compounds integrate specific substituent patterns and molecular configurations that work synergistically to provide extended therapeutic window

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12590072B2Thyromimetics

Publication Date: 2026.03.31 AUTOBAHN THERAPEUTICS INC

AI summary

Disclosed herein are thyromimetic compounds having utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their preparation.