Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
Department of Chemistry, Korea University, Seoul 02841, Korea.
Molecules. 2019 Sep 5;24(18):3234. doi: 10.3390/molecules24183234.
Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT agonists. To improve selectivity for 5-HT over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds and as potent 5-HT agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine showed a highly agonistic effect on the 5-HT receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine could be considered a viable lead compound as a 5-HT selective agonist.
在这里，我们描述了二取代嘧啶衍生物的合成及其作为选择性 5-HT 激动剂的生物学评价。为了提高对 5-HT 的选择性而不是其他亚型，我们合成了两个系列的二取代嘧啶，它们在 5-位或 4-位具有氟苯烷氧基，在 2-位具有不同的环状胺。基于细胞的体外测定和结合测定鉴定出化合物 和 为有效的 5-HT 激动剂。对 5-HT 亚型选择性和类药性的进一步研究表明，2,4-二取代嘧啶 在 5-HT 受体上表现出高度激动作用，具有优异的选择性，以及出色的类药性，包括高血浆和微粒体稳定性，以及低 CYP 抑制。因此，嘧啶 可以被认为是一种可行的先导化合物，作为一种 5-HT 选择性激动剂。
