Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta

Abstract A set of thyromimetics having improved selectivity for TR-β1 were prepared by replacing the 3 ′ -isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3 ′ -phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-β1 LBD shows methionine 442 to be displaced by the bulky R3 ′ phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand–receptor complex retains full agonist activity.