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

DOI Web Site Web Site PubMed 参考文献11件
  • Takahashi Naoki
    Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd.
  • Asano Yukiyasu
    Product Planning II, R&D Planning Department, R&D Strategy Center, Sanwa Kagaku Kenkyusho, Co., Ltd.
  • Maeda Koji
    Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd.
  • Watanabe Nobuhide
    Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd.

書誌事項

タイトル別名
  • <i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

この論文をさがす

抄録

We recently reported that the novel thyroid hormone receptor β (TRβ) 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 TRβ 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 TRβ 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 TRβ 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 TRβ modulators.

収録刊行物

参考文献 (11)*注記

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ