Structure-activity relationship of N,N'-disubstituted pyrimidinetriones as Ca(V)1.3 calcium channel-selective antagonists for Parkinson's disease.
Structure-activity relationship of N,N'-disubstituted pyrimidinetriones as Ca(V)1.3 calcium channel-selective antagonists for Parkinson's disease.
复制标题
DOI：
10.1021/jm4005048
复制
发表时间：
2013-06-13
影响因子：
7.3
通讯作者：
Silverman RB
中科院分区：
文献类型：
--
作者：
Kang S;Cooper G;Dunne SF;Luan CH;Surmeier DJ;Silverman RB
CaV1.3 L型钙通道（LTCCs）是帕金森病的潜在靶点，因为通过该通道的钙离子内流涉及线粒体氧化应激的产生，导致多巴胺能神经元的细胞死亡。选择性抑制CaV1.3而不是其他LTCC亚型，特别是CaV1.2，对于最大限度地减少潜在的副作用至关重要。我们最近发现嘧啶三酮（PYTs）作为CaV1.3选择性支架，在这里，我们报告的结构-活性关系的PYTs与CaV1.3和CaV1.2 LTCC。通过改变PYT的环戊基和芳烷基上的取代基，SAR研究允许表征CaV1.3和CaV1.2 LTCCs结合位点。SAR还确定了保留选择性或增强结合亲和力的四个重要部分。我们的研究代表了PYT在CaV1.3和CaV1.2 LTCC的SAR的显著增强，并强调了这一系列化合物用于药物开发的先导优化和多样化方面的几项进展。
CaV1.3 L-type calcium channels (LTCCs) have been a potential target for Parkinson’s disease since calcium ion influx through the channel was implicated in the generation of mitochondrial oxidative stress, causing cell death in the dopaminergic neurons. Selective inhibition of CaV1.3 over other LTCC isoforms, especially CaV1.2, is critical to minimize potential side effects. We recently identified pyrimidinetriones (PYTs) as a CaV1.3-selective scaffold; here we report the structure-activity relationship of PYTs with both CaV1.3 and CaV1.2 LTCCs. By variation of the substituents on the cyclopentyl and arylalkyl groups of PYT, SAR studies allowed characterization of the CaV1.3 and CaV1.2 LTCCs binding sites. The SAR also identified four important moieties that either retain selectivity or enhance binding affinity. Our study represents a significant enhancement of the SAR of PYTs at CaV1.3 and CaV1.2 LTCCs and highlights several advances in the lead optimization and diversification of this family of compounds for drug development.