Thyroid Receptor Ligands. 3. Design and Synthesis of 3,5-Dihalo-4-alkoxyphenylalkanoic Acids as Indirect Antagonists of the Thyroid Hormone Receptor
- Åsa Hedfors
- ,
- Theresa Appelqvist
- ,
- Bo Carlsson
- ,
- Lars-Göran Bladh
- ,
- Chris Litten
- ,
- Peter Agback
- ,
- Marlena Grynfarb
- ,
- Konrad F. Koehler
- , and
- Johan Malm
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Karo Bio AB, Novum, Huddinge SE-141 57, Sweden
Abstract
Based on the recently described concept of “indirect antagonism” of nuclear receptors, a series of thyroid hormone receptor (TR) antagonists were prepared, in which the outer ring of a thyromimetic was replaced with alkyl chains of variable length and branch. The results of a binding assay for the human TR and reporter cell assay revealed, within this series, a positive correlation between increasing bulk of the alkyl group and affinity to TRs. Compared with already reported TR antagonists, their affinities are within the same range, thus potentially representing a useful approach to novel and high affinity TR-antagonists.
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