Thyroid-Hormone Uptake by Hepatocytes - Structure-Activity-Relationships of Phenylanthranilic Acids with Inhibitory Activity

Chalmers, DK, Scholz, GH, Topliss, DJ, Kolliniatis, E, Munro, Sla, Craik, DJ, Iskander, MN and Stockigt, JR (1993) Thyroid-Hormone Uptake by Hepatocytes - Structure-Activity-Relationships of Phenylanthranilic Acids with Inhibitory Activity. Journal of Medicinal Chemistry, 36 9: 1272-1277. doi:10.1021/jm00061a019


Author Chalmers, DK
Scholz, GH
Topliss, DJ
Kolliniatis, E
Munro, Sla
Craik, DJ
Iskander, MN
Stockigt, JR
Title Thyroid-Hormone Uptake by Hepatocytes - Structure-Activity-Relationships of Phenylanthranilic Acids with Inhibitory Activity
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 1993-04-01
Year available 1993
Sub-type Article (original research)
DOI 10.1021/jm00061a019
Open Access Status Not yet assessed
Volume 36
Issue 9
Start page 1272
End page 1277
Total pages 6
Place of publication WASHINGTON
Publisher AMER CHEMICAL SOC
Language eng
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.
Keyword Binding
Receptor
Protein
Analogs
Drugs
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: ResearcherID Downloads - Archived
 
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