Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TRβ subtype-selective thyromimetics

In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the β 1-isoform of the thyroid receptor family. Structure–activity relationship studies on the 3,5- and 3′-positions provided compounds with enhanced TRβ affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis. Graphic