TSHR Antagonist Compounds With Reduced FSHR Cross-Reactivity
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Solution Overview
Problem
Current treatments for hyperthyroidism, particularly Graves' disease and Graves' Ophthalmopathy, do not effectively target the thyroid-stimulating hormone receptor (TSHR), leading to adverse effects and therapeutic gaps, and existing small molecule TSHR antagonists exhibit cross-reactivity with the follicle-stimulating hormone receptor (FSHR).
Innovation Solution
Development of novel chemical compounds, specifically stereoisomers and enantiomers with a norbornane/thiazolone structure, that act as TSHR antagonists with reduced cross-reactivity to FSHR, targeting the allosteric binding pocket of the TSHR to inhibit its activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If thyrostatic drugs are used to block thyroid hormone production, then thyroid hormone levels are regulated, but adverse effects occur and the causative molecular activation of TSHR is not targeted
Solution Approach 1:
The invention extracts and targets the specific pathological activation mechanism of TSHR by autoantibodies, separating this causal target from the downstream effects. By developing small allosteric antagonists that directly bind to TSHR, the treatment addresses the root cause rather than merely blocking downstream hormone production, thereby reducing adverse effects while maintaining effectiveness.
Solution Approach 2:
The patent introduces small molecule allosteric antagonists as intermediary compounds that bind to a distinct allosteric site on TSHR rather than competing with autoantibodies for the orthosteric site. This intermediary approach allows selective modulation of receptor activity without directly interfering with autoantibody binding, providing a new therapeutic mechanism that reduces adverse effects.
2Reliability
If existing anti-thyroid drugs are used, then thyroid hormone synthesis is inhibited, but TSHR activation by autoantibodies is not directly targeted
Solution Approach 1:
The invention extracts the specific target of pathological activation (TSHR) from the complex downstream signaling cascade. By focusing on TSHR as the primary target and developing direct antagonists, the treatment simplifies the therapeutic mechanism while improving reliability by addressing the root cause of Graves' disease.
3Reliability
If small allosteric antagonists are developed for TSHR, then direct targeting of TSHR is achieved, but such compounds are not yet available on the market
Solution Approach 1:
The patent applies parameter changes by developing small molecule compounds with specific molecular properties that allow them to bind allosterically to TSHR. By optimizing parameters such as molecular size, binding affinity, and selectivity, the invention creates compounds that are both therapeutically effective and suitable for pharmaceutical development and manufacturing.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These compounds provide effective treatment for hyperthyroidism, including Graves' disease and Ophthalmopathy, with reduced side effects by specifically inhibiting TSHR activation, thus offering a therapeutic advantage over existing treatments.
Implementation Method 1
TSH binds to its receptor and leads to the stimulation of second messenger pathways involving predominantly cAMP
Data Source
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AI summary
The invention relates to chemical compounds that are useful in the treatment of a subject afflicted by a thyroid disease, in particular to compounds that exhibit activity as thyroid-stimulating hormone receptor (TSHR) antagonists and their use in the treatment of hyperthyroidism, Graves' disease, Graves' Ophthalmopathy and thyroid cancer.