The sodium iodide symporter (NIS) is responsible for the accumulation of iodide in the thyroid gland. This transport process is involved in numerous thyroid dysfunctions and is the basis for human contamination in the case of exposure to radioactive iodine species. 4‐Aryl‐3,4‐dihydropyrimidin‐2(1H)‐ones were recently discovered by high‐throughput screening as the first NIS inhibitors. Described herein are the synthesis and evaluation of 115 derivatives with structural modifications at five key positions on the pyrimidone core. This study provides extensive structure–activity relationships for this new class of inhibitors that will serve as a basis for further development of compounds with in vivo efficacy and adequate pharmacokinetic properties. In addition, the SAR investigation provided a more potent compound, which exhibits an IC50 value of 3.2 nM in a rat thyroid cell line (FRTL5).
Ain′t NIS‐behavin′: The effect of structure modification at five key positions on the dihydropyrimidone core is reported against iodide transport in rat thyroid‐derived cells. This work describes extensive structure–activity relationships and identifies the most potent inhibitor reported to date.
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