Structure-based design and synthesis of a thyroid hormone receptor (TR) antagonist.
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.
Baxter
John D
JD
Metabolic Research Unit, University of California, San Francisco, California 94143, USA. jbaxter918@aol.com
Goede
Patrick
P
Apriletti
James W
JW
West
Brian L
BL
Feng
Weijun
W
Mellstrom
Karin
K
Fletterick
Robert J
RJ
Wagner
Richard L
RL
Kushner
Peter J
PJ
Ribeiro
Ralff C J
RC
Webb
Paul
P
Scanlan
Thomas S
TS
Nilsson
Stefan
S
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
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