The selenium analog of methimazole. Measurement of its inhibitory effect on type I 5'-deiodinase and of its antithyroid activity.

Methimazole (MMI), unlike propylthiouracil (PTU) is a poor inhibitor of type I iodothyronine deiodinase (ID-1). Inhibition of the enzyme by PTU was attributed initially to formation of a mixed disulfide between PTU and a cysteine residue at the active site. Presumably, MMI was unable to form a stable mixed disulfide and thus did not inhibit the enzyme. However, it has been demonstrated recently that ID-1 is a selenium-containing enzyme, with selenocysteine, rather than cysteine, at the active site. This observation raised the possibility that the selenium analog of MMI, methyl selenoimidazole (MSeI), might be a better inhibitor of ID-1 than MMI itself, as formation of the Se-Se bond with the enzyme would be expected to occur more readily than formation of the S-SE bond. To test this possibility, we developed a procedure for the synthesis of MSeI and compared MSeI with MMI and PTU for inhibition of ID-1 and for antithyroid activity. For inhibition of ID-1, MMI and MSeI were tested at concentrations of 10-300 microM. No significant inhibition was observed with MMI. MSeI showed slight but significant inhibition only in the 100-300 microM range. PTU, on the other hand, showed marked inhibition at 1 microM. Thus, replacement of the sulfur in MMI with selenium only marginally increases its inhibitory effect on ID-1. As an inhibitor of ID-1, MSeI is much less than 1% as potent as PTU. MMI and MSeI were also compared for antithyroid activity, both in vivo and in vitro. As an inhibitor of the catalytic activity of thyroid peroxidase, MMI was 4-5 times more potent than MSeI in a guaiacol assay, but only twice as potent in an iodination assay. In in vivo experiments with rats, MMI was at least 50 times more potent than MSeI in inhibiting thyroidal organic iodine formation. The relatively low potency of MSeI in vivo suggests that it is much less well concentrated by the thyroid than in MMI.