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Thyroid hormone uptake by hepatocytes: structure-activity relationships of phenylanthranilic acids with inhibitory activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1993 Apr 30; Vol. 36 (9), pp. 1272-7. - Publication Year :
- 1993
-
Abstract
- 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.
- Subjects :
- Animals
Chemical Phenomena
Chemistry, Physical
Flufenamic Acid pharmacology
Liver drug effects
Liver Neoplasms, Experimental
Meclofenamic Acid pharmacology
Mefenamic Acid pharmacology
Molecular Structure
Rats
Structure-Activity Relationship
Tumor Cells, Cultured
ortho-Aminobenzoates pharmacology
Liver metabolism
Triiodothyronine metabolism
ortho-Aminobenzoates chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 36
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 8487264
- Full Text :
- https://doi.org/10.1021/jm00061a019