Thyroid hormone uptake by hepatocytes: Structure-activity relationships of phenylanthranilic acids with inhibitory activity

Article abstract of DOI:10.1021/jm00061a019

The synthesis of a series of mono- and disubstituted N-phenylanthranilic acids is described. Substituents on the phenyl ring include Cl, CN, OH, CF₃, Br, I, CH₃, OCH₃, and OCF₂CF₂H. These compounds have been tested for their inhibitory effect on triiodothyronine (T₃) uptake by H4 hepatocytes. The nonsteroidal antiinflammatory drugs flufenamic acid, mefenamic acid, and meclofenamic acid and the structurally related compounds 2,3- dimethyldiphenylamine and diclofenac were also tested. The most potent compounds were found to be, in order of decreasing activity, meclofenamic acid (2,6-Cl₂,3-CH₃), flufenamic acid (3-CF₃), mefenamic acid (2,3- (CH₃)₂), and the compounds with 3,5-Cl₂ and 3-OCF₂CF₂H substituents. The least potent compounds had 3-CN and 3-OH substituents. An analysis of quantitative structure-activity relationships (QSAR) for the series of phenylanthranilic acids showed that the inhibition of T₃ uptake is highly dependent on the hydrophobicity of the compound. The relationship between uptake inhibition and the calculated octanol-water partition coefficient (clogP) was found to be parabolic, with optimum inhibitory activity found when the clogP of the phenylanthranilic acid was 5.7. It was also found that the 1-carboxylic acid group of the phenylanthranilic acids was not a prerequisite for uptake inhibition to occur, but its removal or alteration resulted in reduced inhibition.