In Vivo Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

We recently reported that the novel thyroid hormone receptor beta (TR beta) selective agonists SKL-12846 and SKL-13784 reduce blood cholesterol levels without affecting thyroid-stimulating hormone (TSH) in cholesterol-fed rats. Our aim in this study was to elucidate what sets apart these SKL-compounds as TR beta agonists with no effect on TSH. To this end, we determined SKL-compounds pharmacokinetics and tissue distribution in normal rats and compared them to those of GC-1, a liver-selective TR beta agonist with concomitant effect on TSH. The present study explains why SKL-12846 and SKL-13784 have beneficial effects on lowering lipids without affecting heart rate and TSH production at the therapeutic dose in cholesterol-fed rats. In addition, we found that SKL-13784 shows no sign of escape phenomenon in fructose-fed rats. These results demonstrate the advantages of extremely high liver specificity to TR beta agonists. However, SKL-13784 has been found significantly to reduce endogenous T-4 levels at doses lower than its lipid-lowering dose, which may raise concerns over this compound's ability to alter thyroid hormone metabolism in the liver. While the mechanism by which SKL-13784 reduces endogenous T-4 levels is still unclear, our results would help design better liver-selective TR beta modulators.