Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta.
Article Details
- CitationCopy to clipboard
Hangeland JJ, Doweyko AM, Dejneka T, Friends TJ, Devasthale P, Mellstrom K, Sandberg J, Grynfarb M, Sack JS, Einspahr H, Farnegardh M, Husman B, Ljunggren J, Koehler K, Sheppard C, Malm J, Ryono DE
Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta.
Bioorg Med Chem Lett. 2004 Jul 5;14(13):3549-53.
- PubMed ID
- 15177471 [ View in PubMed]
- Abstract
A set of thyromimetics having improved selectivity for TR-beta1 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-beta1 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) KB-141 Thyroid hormone receptor alpha IC 50 (nM) 25 7 4 Details KB-141 Thyroid hormone receptor beta IC 50 (nM) 1.1 7 4 Details Liothyronine Thyroid hormone receptor alpha IC 50 (nM) 0.24 7 4 Details Liothyronine Thyroid hormone receptor beta IC 50 (nM) 0.26 7 4 Details