Design, Synthesis And Biological Evaluation Of CCR4Antagonists

CC chemokine receptor4（CCR4） is a seven-transmembrane G-protein-coupledreceptor that is selectively expressed on Th2cell membranes. It is a pivotal factor inthe development of allergic inflammations, such as asthma, dermatitis, and rhinitis.CCR4has three natural ligands: thymus and activation regulated chemokine（TARC/CCL17）; macrophage-derived chemokine （MDC/CCL22） and chemokine-likefactor1（CKLF1）. Through the chemotaxis of the three ligands of CCR4, the Th2cells are attracted to the sites of allergic inflammation. The number of MDC, TARC,and CCR4-expressing T cells is increased in asthmatic lungs and airways. In murineasthmatic models, the CCR4blocking antibody attenuates airway eosinophilia andgoblet cell hyperplasia and diminishes IgE synthesis and bronchial hyperreactivity.Similar to the CCR4antibody, the special Ab against TARC and MDC can alsoreduce airway eosinophilia and hyperresponsiveness in asthmatic mice elicited byOVA. Furthermore, CCR4knockout mice treated with Mycobacterium bovisBacille–Calmette–Guerin experience a two-week delay in bacterial clearance anddiminished late-stage inflammation. Intramuscular injection of CKLF1plasmid DNAinto BALB/c mice induces dramatic pathological changes in the lungs of the micewhich are similar to those observed in human asthma. Therefore, CCR4and its threeligands （TARC, MDC, and CKLF1） play important roles in allergic inflammations,and CCR4is a ideal target point to design and find drugs of the allergic diseases.According to the structure-activity relationship of CCR4antagonists, wedesigned and synthesized a series of piperazine pyrimidine derivatives （40newcompouds）. And Their activities were evaluated using a CCR4-MDC/TARC/C27chemotaxis inhibition assay. BMS-397was used as the calibration or comparison standard for the results in all the assays, compounds2and15demonstrate betterchemotaxis inhibition activities for MDC, TARC, and C27compared with BMS-397.The structure-activity relationship was analyzed which is theory foundation anddirection for the design of better active compouds. In the murine rhinitis model,budesonide was used as the calibration or comparison standard to assess the relativeefficacy of the compounds. The efficacy of1.28mg·kg^-1of budesonide in reducingthe number of sneezing and rubbing nose, and the IL-4level in the bronchoalveolarlavage fluid, and the infiltration of eosinophils in the nasal and pulmonary tissues wasachieved by only10μg·kg^-1of compound2or1μg·kg^-1of compound15.