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

Abstract

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 by1H NMR,13C NMR,MS and elemental analysis.The activities of all the newly synthesized compounds were evaluated using a chemotaxis 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) × 104L / mol.