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Endocrinology Vol. 143, No. 2 517-524
Copyright © 2002 by The Endocrine Society

TRH-TSH-THYROID

Structure-Based Design and Synthesis of a Thyroid Hormone Receptor (TR) Antagonist

John D. Baxter, Patrick Goede, James W. Apriletti, Brian L. West, Weijun Feng, Karin Mellstrom, Robert J. Fletterick, Richard L. Wagner, Peter J. Kushner, Ralff C. J. Ribeiro, Paul Webb, Thomas S. Scanlan and Stefan Nilsson

Departments of Medicine (J.D.B., P.J.K., R.C.J.R.), Biochemistry and Biophysics (R.J.F., R.L.W.), Pharmaceutical Chemistry (T.S.S.), and Cellular and Molecular Pharmacology (R.J.F., T.S.S.), Metabolic Research Unit (J.D.B., J.W.A., B.L.W., W.F., P.W.), and the Diabetes Center (J.D.B, J.W.A., B.L.W., W.F., P.W.), University of California, San Francisco, California 94143; and Karo Bio AB (P.G., K.M., S.N.), Novum, 141 57 Huddinge, Sweden

Address all correspondence and requests for reprints to: John D. Baxter, Metabolic Research Unit, Box 0540, University of California, San Francisco, California 94143-0540. E-mail: jbaxter918{at}aol.com

Antagonists have been developed for several nuclear receptors but not for others, including TRs. TR antagonists may have significant clinical utility for treating hormone excess states and other conditions. A structure derived "extension hypothesis" was applied to synthesize a TR antagonist. The principal design feature was to attach an extension group to a TR agonist whose structure would perturb formation of the TR coactivator-binding surface. The compound, 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid, has no (TR{alpha}) or very weak partial (TRß) TR agonist activity and blocks TR binding of T3, formation of the coactivator-binding surface, and both a positive T3 response on a thyroid hormone response element and a negative T3 response on the TSHß promoter in cultured cells. The results suggest that 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid is a TR antagonist for thyroid hormone response element-mediated responses, this approach can be used more generally to generate nuclear receptor antagonists, and this compound or analogues may have medical and research utility.




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