title: Design and characterization of a thyroid hormone receptor alpha (TRalpha)-specific agonist.
abstract: 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 .
authors.affiliation: Chemistry and Chemical Biology Graduate Program and the Department of Pharmaceutical Chemistry, University of California-San Francisco, 600 16th Street, San Francisco, California 94143-2280, USA.
authors.forename: Cory A
authors.initials: CA
authors.lastname: Ocasio
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology*; D007700:Kinetics; D008956:Models, Chemical; D011485:Protein Binding; D020033:Protein Isoforms; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists* / Q000378:metabolism; D013963:Thyroid Hormones / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution; D015533:Transcriptional Activation; D014981:Xenopus
chemical_list: C517607:5-(3,5-diiodo-4-(3-isopropyl-4-hydroxyphenoxy)benzyl)imidazolidine-2,4-dione; D006827:Hydantoins; D020033:Protein Isoforms; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones