title: Synthesis and biological activity of novel thyroid hormone analogues: 5'-aryl substituted GC-1 derivatives.
abstract: Compounds that selectively modulate thyroid hormone action by functioning as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) might be useful for medical therapy. We have synthesized a high affinity TRbeta-selective agonist ligand, GC-1, and optimized the synthetic route to provide large quantities of the compound for animal testing. In addition to an improvement in efficiency, the new synthetic route offers a chemical handle for selective modification of the thyronine skeleton to produce new derivatives. To explore the effect of GC-1 core structure modifications on binding to TR isoforms and activation of transcription, we developed here an efficient and flexible route to a new series of 5'-substituted GC-1 analogues. This route relies on ortho lithiation and in situ boration of the biarylmethane compound 1, a key intermediate of the revised GC-1 synthesis, followed by Suzuki cross-coupling. Using this approach we prepared and tested eleven 5'-substituted GC-1 analogues. Substitution at the 5'-position decreased binding affinity, but retained TRbeta-selectivity for most of the compounds. Transactivation assays reveal that most of these compounds function as thyroid hormone agonists, but one compound (GC-14) antagonizes the response to thyroid hormone.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143-0446, USA.
authors.forename: Grazia
authors.initials: G
authors.lastname: Chiellini
authors.forename: Ngoc Ha
authors.initials: NH
authors.lastname: Nguyen
authors.forename: James W
authors.initials: JW
authors.lastname: Apriletti
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D000085:Acetates; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D010636:Phenols; D011988:Receptors, Thyroid Hormone / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000737:chemistry*; D015533:Transcriptional Activation
chemical_list: D000085:Acetates; D001713:Biphenyl Compounds; D002264:Carboxylic Acids; C413355:GC 1 compound; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones