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Inhibitors of the Interaction of a Thyroid Hormone Receptor and Coactivators:  Preliminary Structure−Activity Relationships

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Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, and University of California San Francisco, Department Biochemistry and Biophysics, 600 Sixteenth Street, San Francisco, California 94143
Cite this: J. Med. Chem. 2007, 50, 22, 5269–5280
Publication Date (Web):October 5, 2007
https://doi.org/10.1021/jm070556y
Copyright © 2007 American Chemical Society

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    Abstract

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    The modulation of gene regulation by blocking the interaction between the thyroid receptor (TR) and obligate coregulators has been reported recently with the discovery of the lead compound 3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one). Herein we report studies aimed at optimization of this initial hit to determine the basic parameters of the structure−activity relationships and clarify the mechanism of action. These studies provided new insights, showing that activity and TRβ isoform selectivity is highly correlated with the structural composition of these covalent inhibitors.

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     St. Jude's Children's Research Hospital.

     University of California, San Francisco.

    *

     Corresponding author. Address:  St. Jude Children's Research Hospital, Department of Chemical Biology and Therapeutics, 332 N. Lauderdale St., Memphis TN 38104-2794. Tel:  (901) 495 5714. Fax:  (901) 495-5715. E-mail:  [email protected].

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    Experimental procedures and characterization data for 3bk, 4ag, 5cf, 6cf, 6bm, 7bg, 8b, and 8e. This material is available free of charge via the Internet at http://pubs.acs.org.

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