Synthesis of 6-anilino-2-thiouracils and their inhibition of human placenta iodothyronine deiodinase

• Published in: Journal of medicinal chemistry 1985-11, Vol.28 (11), p.1692-1694
• Main Authors: Nogimori, T, Emerson, C. H, Braverman, L. E, Wu, C. F, Gambino, J, Wright, G. E
• Format: Article
• Language: English
• Subjects: Chemical Phenomena; Chemistry; Dithiothreitol - pharmacology; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Iodide Peroxidase - antagonists & inhibitors; Organic chemistry; Placenta - enzymology; Pregnancy; Preparations and properties; Propylthiouracil - pharmacology; Structure-Activity Relationship; Thiouracil - analogs & derivatives; Thiouracil - chemical synthesis; Thiouracil - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00149a026

Several 6-anilino-2-thiouracils were synthesized and tested for their ability to inhibit the inner-ring iodothyronine deiodinase from human placenta. The p-ethyl and p-n-butyl analogues were strongly inhibitory to the enzyme and were much more effective than the standard deiodinase inhibitor, 6-propyl-2-thiouracil. The degree of inhibition caused by 6-(p-n-butylanilino)-2-thiouracil was, moreover, unaffected by high concentrations of reducing agent in the enzyme assay. Attempts to prepare 3-alkyl derivatives via S-debenzylation of 2-benzylthio intermediates led to rearrangement to, for example, 3-methyl-5-benzyl-6-amino-2-thiouracil. This compound also strongly inhibited the deiodinase reaction. Preliminary results suggest that these compounds are useful to study in vitro and in vivo metabolism of thyroid hormones and may be clinically useful to enhance the availability of active thyroid hormones to certain organs.