Design and characterization of a thyroid hormone receptor alpha (TRalpha)-specific agonist

Thyroid hormone is a classical endocrine signaling molecule that regulates a diverse array of physiological processes ranging from energy metabolism to cardiac performance. The active form of thyroid hormone, 3,5,3'-triiodo- l -thyronine or T 3 , exerts many of its actions through its receptor, the thyroid hormone receptor (TR), of which there are two subtypes for two isoforms: TRalpha 1 , TRalpha 2 , TRbeta 1 , and TRbeta 2 . Although TR isoforms, with the exception of TRbeta 2 , are expressed in all tissues, they display different patterns of expression in different tissues, giving rise to tissue-specific isoform actions. Currently, several TRbeta-selective agonists have been developed; however, TRalpha-selective agonists have remained elusive. Herein, we report the synthesis and biological evaluation of CO23, the first potent thyromimetic with TRalpha-specific effects in vitro and in vivo .