Se- and s-based thiouracil and methimazole analogues exert different inhibitory mechanisms on type 1 and type 2 deiodinases.
The thioamide anti-thyroid drugs methimazole (MMI) and propylthiouracil (PTU) play a pivotal role in the treatment of hyperthyroidism. MMI exerts its effect via inhibiting one of the key enzymes involved in synthesis of thyroid hormones (TH), thyroid peroxidase (TPO). PTU is both an inhibitor of TPO and type 1 deiodinase (D1), which catalyzes TH deiodination at both aromatic rings. In contrast, no selective inhibitors are known for type 2 deiodinase (D2) or type 3 deiodinase, which deiodinate TH at the phenolic or tyrosyl ring, respectively. We aimed to identify specific inhibitors for D1 or D2. New Se- and S-based PTU and MMI-like compounds have been generated. The D1 and D2 inhibiting capacity of several compounds was tested in vitro. Our data show that compounds based on a PTU and MMI backbone can differentially influence the reaction kinetics of deiodinases. For inhibition of D1, the addition of a phenyl group to the PTU backbone increases potency by at least 10-fold over PTU. For inhibition of D2, the addition of an aromatic ring structure to MMI and its Se isomer increases inhibitory potency by an order of magnitude. Furthermore, S-methylation of the MMI changes its reaction kinetics from non-competitive to uncompetitive with respect to the cofactor dithiothreitol. These results open perspectives for further investigations on identifying specific inhibitors of the deiodinase isoenzymes, potentially based on the addition of aromatic ring structures or alkyl groups to PTU and MMI.
Institut für Experimentelle Endokrinologie, Charité-Universtätsmedizin Berlin, Berlin, Germany.
Eddy
E
Rijntjes
Institut für Experimentelle Endokrinologie, Charité-Universtätsmedizin Berlin, Berlin, Germany.
Philip Moritz
PM
Scholz
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India.
Govindasamy
G
Mugesh
Institut für Experimentelle Endokrinologie, Charité-Universtätsmedizin Berlin, Berlin, Germany.
Josef
J
Köhrle
Deiodinase; Inhibitor; Methimazole; Propylthiouracil; Selenium; Thyroid; Thyrostatic compounds