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 , which is a potent TRβ agonist (EC: 21.0 nM, 85.0% of the maximum efficacy of ) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβ mutant. Then, we developed a highly efficient synthetic method for . Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, 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).