PDE-4抑制剂的设计、合成及生物活性研究
收稿日期: 2017-05-31
修回日期: 2017-09-23
网络出版日期: 2017-10-11
基金资助
十二五国家科技重大专项（No.2012ZX09401-006）资助项目.
Design, Synthesis, and Biological Evaluation of Novel PDE-4 Inhibitors
Received date: 2017-05-31
Revised date: 2017-09-23
Online published: 2017-10-11
Supported by
Project supported by the National Science and Technology Major Project in 12th Five-Year (No. 2012ZX09401-006).
依据药效团原理，对已报道的磷酸二酯酶（PDE-4）抑制剂Crisaborole进行结构修饰和改造，设计并合成了7个全新的小分子化合物，其结构经1H NMR、13C NMR和HRMS确证.研究其对磷酸二酯酶-4A（PDE-4A）的抑制活性、抑制炎症因子TNF-α释放效果以及抗炎活性.结果表明，所设计的7个化合物均表现出良好生物活性，其中一个化合物活性明显优于阳性对照药.
关键词： PDE-4抑制剂; Crisaborole; 合成; 抗炎
高粟繁 , 许勤龙 , 李家明 , 储昭兴 , 何广卫 , 林高峰 , 朱正伟 , 崔勇 , 莫佳佳 , 郭敬 , 赵炎 . PDE-4抑制剂的设计、合成及生物活性研究[J]. 有机化学, 2018 , 38(2) : 478 -485 . DOI: 10.6023/cjoc201705042
Based on the reported phosphodiesterase-4(PDE-4) inhibitor of crisaborole, seven compounds with structural novelty were designed and synthesized according to the pharmacophore-combination strategy. The structures of them were identified by NMR and HRMS. Their inhibitory activities against phosphodiesterase-4A (PDE-4A) have been investigated. The inhibitory activities of inflammatory factor induced by lipopolysaccharide (LPS) or phorbol ester have been measured by mouse model. The results showed that all compounds exhibited high anti-inflammatory activities. In particular, one compound activity was significantly better than that of positive control drug.
Key words： PDE-4 inhibitor; crisaborole; synthesis; anti-inflammatory
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