THYROID-HORMONE UPTAKE BY HEPATOCYTES - STRUCTURE-ACTIVITY-RELATIONSHIPS OF PHENYLANTHRANILIC ACIDS WITH INHIBITORY ACTIVITY

The synthesis of a series of mono- and disubstituted N-phenylanthranil ic acids is described. Substituents on the phenyl ring include Cl, CN, OH, CF3, Br, I, CH3, OCH3, and OCF2CF2H. These compounds have been te sted 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 co mpounds 2,3-dimethyldiphenylamine and diclofenac were also tested. The most potent compounds were found to be, in order of decreasing activi ty, meclofenamic acid (2,6-Cl2,3-CH3), flufenamic acid (3-CF3), mefena mic acid (2,3-(CH3)2), and the compounds with 3,5-Cl2 and 3-OCF2CF2H s ubstituents. 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 o f 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 o ptimum inhibitory activity found when the clogP of the phenylanthranil ic acid was 5.7. It was also found that the 1-carboxylic acid group of the phenylanthranilic acids was not a prerequisite for uptake inhibit ion to occur, but its removal or alteration resulted in reduced inhibi tion.