title: Structure-based design and synthesis of a thyroid hormone receptor (TR) antagonist.
abstract: 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 (TRalpha) or very weak partial (TRbeta) 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 TSHbeta 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.
authors.affiliation: Metabolic Research Unit, University of California, San Francisco, California 94143, USA. jbaxter918@aol.com
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Patrick
authors.initials: P
authors.lastname: Goede
authors.forename: James W
authors.initials: JW
authors.lastname: Apriletti
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Weijun
authors.initials: W
authors.lastname: Feng
authors.forename: Karin
authors.initials: K
authors.lastname: Mellstrom
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wagner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kushner
authors.forename: Ralff C J
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
authors.forename: Stefan
authors.initials: S
authors.lastname: Nilsson
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology*; D001970:Bromobenzoates; D016466:CHO Cells; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D003461:Crystallography; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter; D005822:Genetic Vectors; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D010647:Phenyl Ethers; D010920:Placenta / Q000201:enzymology; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C447820:3,5'-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid; D001565:Benzoates; D001970:Bromobenzoates; D006727:Hormone Antagonists; D010647:Phenyl Ethers; D011988:Receptors, Thyroid Hormone; D000469:Alkaline Phosphatase