Synthesis and biological activity of novel thyroid hormone analogues: 5′-aryl substituted GC-1 derivatives Original Research Article

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 TRβ-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 TRβ-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.