Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor β Agonist

The design and development of agonists
selectively targeting thyroid
hormone receptor β (TRβ) and TRβ mutants remain
challenging tasks. In this study, we first adopted the strategy of
breaking the “His-Phe switch” to solve two problems,
simultaneously. A structure-based design approach was successfully
utilized to obtain compound 16g, which is a potent TRβ
agonist (EC50: 21.0 nM, 85.0% of the maximum efficacy of 1) with outstanding selectivity for TRβ over TRα
and also effectively activates the TRβH435R mutant.
Then, we developed a highly efficient synthetic method for 16g. Our serials of cocrystal structures revealed detailed structural
mechanisms in overcoming subtype selectivity and rescuing the H435R
mutation. 16g also showed excellent lipid metabolism,
safety, metabolic stability, and pharmacokinetic properties. Collectively, 16g is a well-characterized selective and mutation-sensitive
TRβ agonist for further investigating its function in treating
dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance
to thyroid hormone (RTH).