Discovery of novel indane derivatives as liver-selective thyroid hormone receptor beta (TRbeta) agonists for the treatment of dyslipidemia.

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Shiohara H, Nakamura T, Kikuchi N, Ozawa T, Nagano R, Matsuzawa A, Ohnota H, Miyamoto T, Ichikawa K, Hashizume K

Discovery of novel indane derivatives as liver-selective thyroid hormone receptor beta (TRbeta) agonists for the treatment of dyslipidemia.

Bioorg Med Chem. 2012 Jun 1;20(11):3622-34. doi: 10.1016/j.bmc.2012.03.056. Epub 2012 Apr 11.

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22542282 [ View in PubMed

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Abstract

Thyromimetics that specifically target TRbeta have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRbeta) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRbeta selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Liothyronine	Thyroid hormone receptor alpha	Ki (nM)	2.33	N/A	N/A	Details
Liothyronine	Thyroid hormone receptor beta	Ki (nM)	2.29	N/A	N/A	Details