Deuterated THR-β Modulators for MASH Treatment
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Solution Overview
Problem
Metabolic dysfunction-associated steatohepatitis (MASH) and related conditions such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, and thyroid disorders lack effective treatments to halt progression and reverse fibrosis, which are critical for preventing liver failure and hepatocellular carcinoma.
Innovation Solution
Development of deuterated thyroid hormone receptor beta (THR-β) modulators, which selectively target THR-β to modulate metabolic pathways, administered alone or in combination with other inhibitors like KHK, FXR agonists, SSAO, FASN, or SCD1 modulators, to treat these conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional THR agonists are used, then metabolic effects are achieved, but cardiac side effects occur due to lack of selectivity
Solution Approach 1:
The patent applies local quality by introducing deuterium atoms at specific positions on the isopropyl group of the THR agonist molecule. This localized isotopic substitution modifies the metabolic stability and selectivity of the compound for THRβ over THRα, thereby improving the therapeutic index while reducing cardiac side effects without altering the overall molecular structure significantly.
Solution Approach 2:
The patent employs parameter changes by replacing hydrogen atoms with deuterium atoms (isotopic substitution) in the isopropyl group. This changes the physical and chemical parameters of the molecule, specifically enhancing metabolic stability and receptor selectivity, which leads to improved therapeutic outcomes with reduced cardiac toxicity.
2Reliability
If THR agonists are used to treat MASH, then metabolic pathways are modulated, but metabolic stability is insufficient with conventional compounds
Solution Approach 1:
The patent utilizes parameter changes through deuterium substitution in the isopropyl group, which slows down metabolic degradation of the compound. This isotopic modification enhances the metabolic stability of the THR agonist, allowing for prolonged therapeutic action and potentially reduced dosing frequency in treating MASH and related disorders.
Data Source
AI summary
Disclosed herein are compounds of Formula I:or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt of the compound, the stereoisomer, or the tautomer; wherein A is an isopropyl group, and 1 to 7 hydrogen atoms on the isopropyl group are replaced with deuterium atom(s); pharmaceutical compositions comprising such compounds, and methods of treating disease by administering or contacting a subject with one or more of the above compounds.