In vivo evaluation of 1-benzyl-4-aminoindole-based thyroid hormone receptor ß agonists: importance of liver selectivity in drug discovery.

We recently reported that the novel thyroid hormone receptor ß (TRß) 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 TRß 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 TRß 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 TRß agonists. However, SKL-13784 has been found significantly to reduce endogenous T4 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 T4 levels is still unclear, our results would help design better liver-selective TRß modulators.

Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor ß agonists.

A series of 1-benzylindole-based TRß agonists were prepared and evaluated. Compounds 11b' and 11c' were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres.