Selective thyroid hormone receptor β agonists with oxadiazolone acid isosteres.
Kirschberg TA,Jones CT,Xu Y,Fenaux M,Halcomb RL,Wang Y,Klucher K
Use of the oxadiazolone acid isostere in triiodothyronine analogs yielded potent and selective agonists for the thyroid hormone receptor β. Selected examples showed good in-vivo efficacy in a rat hypercholesterolemic model. One compound was further profiled in a diet-induced mouse model of nonalcoholic steatohepatitis (NASH) and showed robust target engagement and significant histological improvements in both liver steatosis and fibrosis.