哌嗪嘧啶类CCR4拮抗剂的设计、合成及生物活性  

Design,Synthesis and Biological Activities of a Series of Piperazine Pyrimidine as CCR4 Antagonists

作　　者：巩宏伟[1,2,3] 綦辉[4] 孙薇[1] 姜丹[3] 肖军海[3] 杨晓虹[1] 王应[4] 李松[3] 

机构地区：[1]吉林大学药学院 [2]公共卫生学院,长春130021 [3]军事医学科学院毒物药物研究所,北京100850 [4]北京大学人类疾病基因研究中心,北京100191

出　　处：《高等学校化学学报》2013年第9期2131-2138,共8页Chemical Journal of Chinese Universities

基　　金：国家科技重大专项(批准号:2012ZX09301003);国家自然科学基金(批准号:90813025)资助

摘　　要：基于对已报道的CCR4拮抗剂的构效关系分析,设计并合成了一系列哌嗪嘧啶类化合物.采用细胞趋化抑制实验测试了合成化合物的体外活性,其中化合物8a的活性优于目前报道的活性最好的化合物BMS-397;在小鼠鼻炎模型中,化合物8a以极低的剂量达到了布地奈德(鼻炎临床治疗药物)的治疗效果.采用毛细管电泳法测得化合物8a与CCR4 N端40肽的结合常数为(3.6179±0.5976)×104L/mol.CC chemokine receptor 4 （CCR4） is a pivotal factor in the development of allergic inflammations, such as asthma, dermatitis and rhinitis. CCR4 antagonists have a huge potential in the therapeutics of the allergic diseases, and BMS-397 is the most potent CCR4 antagonists in the reported compounds. The structureactivity relationship of BMS-397 was studied and the large influence of the groups of pyridine and piperidine on the activity led us to modify these two sites. A series of piperazine pyrimidine derivatives was designed and synthesized. Their structures were characterized by 1H NMR, 13C NMR, MS and elemental analysis. The ac- tivities of all the newly synthesized compounds were evaluated using a ehemotaxis inhibition assay. The results of biological activity experiment show that compound 8a was more potent than BMS-397. In the murine rhinitis model, budesonide was used as the calibration or comparison standard to assess the relative efficacy of compound 8a. The results show that compound 8a was more effective than budesonide, revealed excellent affinity to N-terminal of CCR4, and the apparent binding constant of CZE experiment result was （3.6179±0. 5976）×10^4 L/mol.

关 键 词：CCR4拮抗剂 CKLF1 TARC MDC 过敏性炎症 

分 类 号：O625[理学—有机化学]