title: Synthesis and evaluation of 3,4-dihydropyrimidin-2(1H)-ones as sodium iodide symporter inhibitors.
abstract: 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 IC(50)  value of 3.2 nM in a rat thyroid cell line (FRTL5).
authors.affiliation: Department of Bioorganic Chemistry and Isotopic Labelling, CEA, Institute of Biology and Technology (iBiTecS), Gif-sur-Yvette 91191, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lacotte
authors.forename: Celine
authors.initials: C
authors.lastname: Puente
authors.forename: Yves
authors.initials: Y
authors.lastname: Ambroise
mesh_terms: D000818:Animals; D002460:Cell Line; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007454:Iodides / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000099209:Sodium-Iodide Symporters
chemical_list: D004095:Dihydropyridines; D007454:Iodides; D027981:Symporters; D000099209:Sodium-Iodide Symporters