Scaffold hopping delivers quinoline THRβ agonist compound 24 with improved subtype selectivity and liver benefits in MASH models
- Aiming to improve on resmetirom's limited THRβ/THRα selectivity, scaffold hopping produced a new quinoline-based THRβ agonist series.
- SAR optimization gave compound 24, a potent agonist with clear THRβ preference over THRα, good oral bioavailability and higher liver exposure than resmetirom.
- In animal models it improved metabolic parameters and reduced hepatic lipid buildup, inflammation and fibrosis, without evident thyroid-axis disruption or THRα-linked cardiac effects, and was well tolerated at high doses.
💡 Points Based on the abstract
Resmetirom set the bar, so the question is what quinoline buys over its pyridazinone core: selectivity, liver targeting, or just IP space. Compound 24's higher liver exposure is encouraging, but I'd want THRα and THRβ functional data in cell reporter assays, plus OATP-mediated uptake and a look at whether the quinoline raises CYP or hERG liabilities.
Discovery of Quinoline-Based Highly Potent and Selective THRβ Agonists for MASLD Treatment ↗