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

doi:10.7503/cjcu20120607

Abstract

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 structure-activity 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 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)×10⁴ L/mol.

Key words: CCR4 antagonists, Chemokine-like factor 1(CKLF1), Thymus and activation regulated chemokine(TARC), Macrophage-derived chemokine(MDC), Inflammatory disease

CLC Number:

O625

TrendMD:

GONG Hong-Wei, QI Hui, SUN Wei, JIANG Dan, XIAO Jun-Hai, YANG Xiao-Hong, WANG Ying, LI Song. Design, Synthesis and Biological Activities of a Series of Piperazine Pyrimidine as CCR4 Antagonists[J]. Chem. J. Chinese Universities, 2013, 34(9): 2131.

References

[1] Vijayanand P., Durkin K., Hartmann G., Morjaria J., Seumois G., Staples K. J., Hall D., Bessant C., Bartholomew M., Howarth P. H., Friedmann P. S., Djukanovic R., J. Immunol., 2010, 184(8), 4568—4574

[2] Perros F., Hoogsteden H. C., Coyle A. J., Lambrecht B. N., Hammad H., Allergy, 2009, 64(7), 995—1002

[3] Kawasaki S., Takizawa H., Yoneyama H., Nakayama T., Fujisawa R., Izumizaki M., Imai T., Yoshie O., Homma I., Kazuhiko Y., Matsushima K., J. Immunol., 2001, 166(3), 2055—2062

[4] Gonzalo J. A., Pan Y., Lloyd C. M., Jia G. Q., Yu G., Dussault B., Powers C. A., Proudfoot A. E. I., Coyle A. J., Gearing D., Gutierrez J. C., J. Immunol., 1999, 163(1), 403—411

[5] Stolberg V. R., Chiu B. C., Schmidt B. M., Kunkel S. L., Sandor M., Chensue S. W., Am. J. Pathol., 2011, 178(1), 233—244

[6] Imai T., Yoshida T., Baba M., Nishimura M., Kakizaki M., Yoshie O., J. Biol. Chem., 1996, 271(35), 21514—21521

[7] Godiska R., Chantry D., Raport C. J., Sozzani S., Allavena P., Leviten D., Mantovani A., Gray P. W., J. Exp. Med., 1997, 185(9), 1595—1604

[8] Li F., Song Q., Di C., Wang L., Shi Q., Sun R., Xia D., Rui M., Tang J., Ma D., Biochem. J., 2001, 357(P1), 127—135

[9] Tan Y. X., Zhong N. S., Chin. J. Tuberc. Respir. Dis., 2002, 25(7), 433(谭亚夏, 钟南山. 中华结核和呼吸杂志, 2002, 25(7), 433)

[10] Wang Y., Zhang Y., Han W., Li D., Tian L., Yin C., Ma D., Int. J. Biochem. Cell Biol., 2008, 40(5), 909—919

[11] Purandare A. V., Wan H., Somerville J. E., Burke C., Vaccaro W., Yang X., Mcintyre K. W., Poss M. A., Bioorg. Med. Chem. Lett., 2007, 17(3), 679—682

[12] Yokoyama K., Ishikawa N., Igarashi S., Kawano N., Masuda N., Hamaguchi W., Yamasaki S., Koganemaru Y., Hattori K., Miyazaki T., Ogino S., Mastumoto Y., Takeuchi M., Ohta M., Bioorg. Med. Chem., 2009, 17(1), 64—73

[13] Burdi D. F., Chi S., Mattia K., Harrington C., Shi Z., Chen S., Jacutin-Porte J., Bennett R., Carson K., Yin W., Kansra V., Gonzalo J., Coyle A., Jaffee B., Ocain T., Hodge M., Larosa G., Harriman G., Bioorg. Med. Chem. Lett., 2007, 17(11), 3141—3145

[14] Wang X., Xu F., Xu Q., Mahmud H., Houze J., Zhu L., Akerman M., Tonn G., Tang L., Mcmaster B. E., Dairaghi D. J., Schall T. J., Collins T. L., Medina J. C., Bioorg. Med. Chem. Lett., 2006, 16(10), 2800—2803

[15] Newhouse B., Allen S., Fauber B., Anderson A. S., Eary C. T., Hansen J. D., Schiro J., Gaudino J. J., Laird E., Chantry D., Eberhardt C., Burgess L. E., Bioorg. Med. Chem. Lett., 2004, 14(22), 5537—5542

[16] Kuhn C. F., Bazin M., Philippe L., Zhang J., Tylaska L., Miret J., Bauer P. H., Chem. Biol. Drug Des., 2007, 70(3), 268—272

[17] Ho K., Beasley J. R., Belanger L., Black D., Chan J., Dunn D., Hu B., Klon A., Kultgen S. G., Ohlmeyer M., Parlato S. M., Ray P. C., Pham Q., Rong Y., Roughton A. L., Walker T. L., Wright J., Xu K., Xu Y., Zhang L., Webb M., Bioorg. Med. Chem. Lett., 2009, 19(21), 6027—6031

[18] Wang H., Xiao J., Cao D., Zhang X., Yan H., Gong Z., Sun T., Li S., Bioorg. Med. Chem. Lett., 2011, 21(3), 1057—1059

[19] Al-Horani R. A., Mehta A. Y., Desai U. R., Eur. J. Med. Chem., 2012, 54, 771—783

[20] Li G., Wang D., Sun M., Li G., Hu J., Zhang Y., Yuan Y., Ji H., Chen N., Liu G., J. Med. Chem., 2010, 53(4), 1741—1754

[21] Kwak Y. G., Song C. H., Yi H. K., Hwang P. H., Kim J. S., Lee K. S., Lee Y. C., J. Clin. Invest., 2003, 111(7), 1083—1092

[22] Xia Z. N., Li L. X., Chen H., Xiong C. Q., Yang F. Q., Chem. J. Chinese Universities, 2011, 32(4), 851—856(夏之宁, 李丽仙, 陈华, 熊彩侨, 杨丰庆. 高等学校化学学报, 2011, 32(4), 851—856)

[23] Wang N., Liu Z. Y., Hu X. L., Bu F. Q., Zhao X. Z., Chem. J. Chinese Universities, 2011, 32(2), 241—245(王宁, 刘忠英, 胡秀丽, 卜凤泉, 赵学忠. 高等学校化学学报, 2011, 32(2), 241—245)