Selenium analogues of antithyroid drugs--recent developments.
Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase (TPO)/H(2)O(2)/iodide system and deiodinated to its active form (T3) by a selenocysteine-containing enzyme, iodothyronine deiodinase (ID). The activation of thyroid-stimulating hormone (TSH) receptor by auto-antibodies leads to 'hyperthyroidism', a life-threatening disease which is treated by antithyroid drugs such as 6-propyl-2-thiouracil (PTU) and methimazole (MMI). The present review describes the biological activities of a number of S/Se derivatives bearing the methimazole pharmacophore. It is shown that the isosteric substitutions in the existing drugs lead to compounds that can effectively and reversibly inhibit the heme-containing lactoperoxidase (LPO). In contrast to methimazole, the selenium analogue, MSeI, does not interfere with the enzyme directly, but it inhibits LPO by reducing the H(2)O(2) that is required for the oxidation of the Fe-center in LPO. These studies reveal that the degradation of the intracellular H(2)O(2) by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland, as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on H(2)O(2) can reversibly inhibit the thyroid peroxidase, such drugs could be of great importance in the treatment of hyperthyroidism.
Roy
Gouriprasanna
G
Department of Inorganic & Physical Chemistry, Indian Institute of Science, Bangalore 560012, India.
Mugesh
Govindasamy
G
D013956:Antithyroid Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006980:Hyperthyroidism / Q000188:drug therapy / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000187:drug effects / Q000378:metabolism; D007784:Lactoperoxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008713:Methimazole / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D018036:Selenium Compounds / Q000737:chemistry / Q000378:metabolism*; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism
D013956:Antithyroid Agents; D018036:Selenium Compounds; D008713:Methimazole; D007784:Lactoperoxidase; D007453:Iodide Peroxidase