Design, Synthesis and SAR Study of Novel Trisubstituted Pyrimidine Amide Derivatives as CCR4 Antagonists
Libao Xu,
Yang Zhang,
Wenjie Dai,
Ying Wang,
Dan Jiang,
Lili Wang,
Junhai Xiao,
Xiaohong Yang,
Song Li
Affiliations
Libao Xu
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
Yang Zhang
Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing 100191, China
Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing 100191, China
Dan Jiang
Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China
Lili Wang
Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China
Junhai Xiao
Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China
Xiaohong Yang
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
Song Li
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
The design, synthesis and structure-activity relationship studies of some novel trisubstituted pyrimidine amide derivatives prepared as CCR4 antagonists are described. The activities of these compounds were evaluated by the CCR4-MDC chemotaxis inhibition assay. Compound 1, which we have previously reported as a potent antagonist of CCR4, was employed as the positive control. The results indicated that most of the synthesized compounds exhibited some chemotaxis inhibition activity against CCR4. Of these new compounds, compounds 6c, 12a and 12b, with IC50 values of 0.064, 0.077 and 0.069 μM, respectively, showed higher or similar activity compared with compound 1 (IC50 of 0.078 μM). These compounds provide a basis for further structural modifications. The systematic structure-activity relationship of these trisubstituted pyrimidine amide derivatives was discussed based on the obtained experimental data. The results from the SAR study may be useful for identifying more potent CCR4 antagonists.
