Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors.

ABSTRACT: We have previously reported the discovery and preliminary structure activity relationships of a series of beta-aminoketones that disrupt the binding of coactivators to TR. However, the most active compounds had moderate inhibitory potency and relatively high cytotoxicity, resulting in narrow therapeutic index. Additionally, preliminary evaluation of in vivo toxicology revealed a significant dose related cardiotoxicity. Here we describe the improvement of pharmacological properties of thyroid hormone receptor coactivator binding inhibitors. A comprehensive survey of the effects of substitutents in key areas of the molecule was carried out based on mechanistic insight from the earlier report. This study revealed that both electron withdrawing and hydrophobic substituents on the aromatic ring

SUBMITTER: Hwang JY 

PROVIDER: S-EPMC2753520 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature