<i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery
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- Takahashi Naoki
- Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd.
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- Asano Yukiyasu
- Product Planning II, R&D Planning Department, R&D Strategy Center, Sanwa Kagaku Kenkyusho, Co., Ltd.
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- Maeda Koji
- Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd.
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- Watanabe Nobuhide
- Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Co., Ltd.
Bibliographic Information
- Other Title
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- In Vivo Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists : Importance of Liver Selectivity in Drug Discovery
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Abstract
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.
Journal
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- Biological and Pharmaceutical Bulletin
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Biological and Pharmaceutical Bulletin 37 (7), 1103-1108, 2014
The Pharmaceutical Society of Japan
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Details 詳細情報について
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- CRID
- 1390282679611124224
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- NII Article ID
- 130004057416
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- NII Book ID
- AA10885497
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- COI
- 1:STN:280:DC%2BC2cfovVCqtg%3D%3D
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- ISSN
- 13475215
- 09186158
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- NDL BIB ID
- 025543057
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- PubMed
- 24989002
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed