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

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
KB-141Thyroid hormone receptor alphaIC 50 (nM)2574Details
KB-141Thyroid hormone receptor betaIC 50 (nM)1.174Details
LiothyronineThyroid hormone receptor alphaIC 50 (nM)0.2474Details
LiothyronineThyroid hormone receptor betaIC 50 (nM)0.2674Details