UCSF

Thyroid hormone orchestrates a multifarious set of physiological activities ranging from fetal, brain, and skeletal maturation to improving vascular tone and controlling cardiac output. Thyroid hormone elicits its effects by binding to the ligand binding domain of the thyroid hormone receptor (TR) for which there are two subtypes for two isoforms: TRα₁, TRα₂, TRβ₁, and TRβ₂. Although TR isoforms, with the exception of TRβ₂ which is mainly expressed in the pituitary, are ubiquitously expressed, these isoforms are expressed in different ratios in different tissues giving rise to tissue-specific isoform action. Selective thyroid hormone analogues, or selective thyromimetics, that discriminate between these two subtypes would serve as useful chemical tools to gain or refine our understanding of the physiological effects of thyroid hormone. These compounds may also prove useful in the clinic as known thyromimetics (i.e. 3,5-diiodothyroproprionic acid and GC-1) show promise in treating cardiac related diseases and metabolic disorders. One way to generate selective thyromimetics with unique pharmacological profiles is to synthesize a small panel of compounds by employing a bioisosteric replacement strategy. This method entails derivatizing one region of the thyronine backbone, the C₁ region, by incorporation of various heterocycles or carbocycles. This strategy led to the production of a small panel of ligands which were screened in ¹²⁵I-T₃ competitive binding and transactivation assays. After this screen, the TRα-specific ligand CO22 was identified; however, it demonstrated poor binding and potency. Replacing the inner-ring methyl groups of CO22 with iodides led to CO23, the first potent thyromimetic to show TRα-specificity in vitro and in vivo. CO23 showed specificity in TRα-mediated transcription in U2OS and HeLa cells and caused Xenopus laevis tadpoles to experience more extensive and rapid hind leg growth, less larval tissue resorption, greater induction of TRα early genes, and less induction of TRβ early and late genes. It was surmised that the imidazolidinedione moiety of the inner-ring confers TRα-specificity; therefore, to engender ligands with improved specificity the 3' outer-ring position was derivatized. This led to several analogues with less potency than CO23, but with a gain in specificity of up to 2-fold.