Discovery of a Highly Selective and H435R-Sensitive ThyroidHormone Receptor?Agonist br

The design and development of agonists selectively targetingthyroid hormone receptor beta(TR beta) and TR beta mutants remain challenging tasks. Inthis study, wefirst adopted the strategy of breaking the"His-Phe switch"to solvetwo problems, simultaneously. A structure-based design approach was successfullyutilized to obtain compound16g, which is a potent TR beta agonist (EC50: 21.0 nM,85.0% of the maximum efficacy of1) with outstanding selectivity for TR beta overTR alpha and also effectively activates the TR beta H435Rmutant. Then, we developed ahighly efficient synthetic method for16g. Our serials of cocrystal structuresrevealed detailed structural mechanisms in overcoming subtype selectivity andrescuing the H435R mutation.16galso showed excellent lipid metabolism, safety, metabolic stability, and pharmacokineticproperties. Collectively,16gis a well-characterized selective and mutation-sensitive TR beta agonist for further investigating its functionin treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH).