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Vol. 26 No. 22 (2014): Vol 26 Issue 22

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Synthesis and Biological Activity of Chiral Rho Kinase Inhibitors

https://doi.org/10.14233/ajchem.2014.17646
Hang Li
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China
Changhai Sun
Tianjin Chase Sun Pharmaceutical Co., LTD, Tianjin 301700, P.R. China
Xinran Wang
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
Shende Jiang
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China
Ligong Chen
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
Xilong Yan
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China

Corresponding Author(s) : Xilong Yan

yan@tju.edu.cn

Asian Journal of Chemistry, Vol. 26 No. 22 (2014): Vol 26 Issue 22

Abstract

It was found that (S)-6H-1-(5-isoquinolinesulfonyl)-2-hydroxymethyl-1-pyrrolidine and (S)-6H-1-(5- isoquinolinesulfonyl)-2-chloromethyl-1-pyrrolidine displayed excellent Rho inhibitory activity in previous work. Therefore, with these two compounds as lead compounds, we designed and synthesized their enantiomers in order to reveal the effects of chirality on the combination of inhibitor and Rho kinase. Their biological activity evaluation results indicated that the chirality of inhibitors indeed presented important influences on their Rho kinase inhibitory activities. Furthermore, several analogues of the lead compounds were designed and synthesized. It was found that the isostere, (S)-6H-1-(5-isoquinolinesulfonyl)-2-fluorinated-methyl-pyrrolidine (compound 7) exhibited much better Rho kinase inhibitory activity than the lead compounds and strongly promoted synapse formation. Thus, it is believed to be a potential candidate as Rho kinase inhibitors.

Keywords

Rho kinase inhibitors Fasudil Biological activity Synapse formation
Li, H., Sun, C., Wang, X., Jiang, S., Chen, L., & Yan, X. (2014). Synthesis and Biological Activity of Chiral Rho Kinase Inhibitors. Asian Journal of Chemistry, 26(22), 7711–7715. https://doi.org/10.14233/ajchem.2014.17646
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References
  1. J.K. Liao, M. Seto and K. Noma, J. Cardiovasc. Pharmacol., 50, 17 (2007); doi:10.1097/FJC.0b013e318070d1bd.
  2. I.A. Abdel-Hamid, Drug Discov. Today, 10, 1459 (2005); doi:10.1016/S1359-6446(05)03596-8.
  3. A. Masumoto, M. Masahiro, H. Shimokawa, L. Urakami, M. Usui and A. Takeshita, Circulation, 105, 1545 (2002); doi:10.1161/hc1002.105938.
  4. V.P. Rao and D.L. Epstein, BioDrugs, 21, 167 (2007); doi:10.2165/00063030-200721030-00004.
  5. H. Tokushige, M. Inatani, S. Nemoto, H. Sakaki, K. Katayama, M. Uehata and H. Tanihara, Invest. Ophthalmol. Vis. Sci., 48, 3216 (2007); doi:10.1167/iovs.05-1617.
  6. I. Cicha, M. Goppelt-Struebe, S. Muehlich, A. Yilmaz, D. Raaz, W.G. Daniel and C.D. Garlichs, Atherosclerosis, 196, 136 (2008); doi:10.1016/j.atherosclerosis.2007.03.016.
  7. M. Kobayashi, H. Kume, T. Oguma, Y. Makino, Y. Ito and K. Shimokata, Clin. Exp. Allergy, 38, 135 (2008); doi:10.1111/j.1365-2222.2007.02879.x.
  8. B.K. Mueller, H. Mack and N. Teusch, Nat. Rev. Drug Discov., 4, 387 (2005); doi:10.1038/nrd1719.
  9. L. Yin, K. Morishige, T. Takahashi, K. Hashimoto, S. Ogata, S. Tsutsumi, K. Takata, T. Ohta, J. Kawagoe, K. Takahashi and H. Kurachi, Mol. Cancer Ther., 6, 1517 (2007); doi:10.1158/1535-7163.MCT-06-0689.
  10. K. Noma, N. Oyama and J.K. Liao, Am. J. Physiol. Cell Physiol., 290, 661 (2005); doi:10.1152/ajpcell.00459.2005.
  11. J. Taniguchi, S. Sawai, M. Mori, T. Kubo, K. Kanai, S. Misawa, S. Isose, T. Yamashita and S. Kuwabara, Ann. Neurol., 66, 694 (2009); doi:10.1002/ana.21784.
  12. B.S.P. Takekazu Kubo, B.S.P. Katsuhiko Hata, B.S.P. Atsushi Yamaguchi and B.S.P. Toshihide Yamashita, Curr. Pharm. Des., 13, 2493 (2007); doi:10.2174/138161207781368657.
  13. S. Tang, Y.J. Shen, M.E. DeBellard and G. Mukhopadhyay, J. Cell. Biol., 138, 1355 (1997); doi:10.1083/jcb.138.6.1355.
  14. S. Tang, R.W. Woodhall, Y.J. Shen, M.E. deBellard, J.L. Saffell, P. Doherty, F. Walsh and M.T. Filbin, Mol. Cell. Neurosci., 9, 333 (1997); doi:10.1006/mcne.1997.0633.
  15. T. Yamashita, M. Fujitani, S. Yamagishi, K. Hata and F. Mimura, Mol. Neurobiol., 32, 105 (2005); doi:10.1385/MN:32:2:105.
  16. P. Lingor, N. Teusch, K. Schwarz, R. Mueller, H. Mack, M. Bahr and B.K. Mueller, J. Neurochem., 103, 181 (2007); doi:10.1111/j.1471-4159.2007.04756.x.
  17. Z. Zhang, A.K. Ottens, S.F. Larner, F.H. Kobeissy, M.L. Williams, R.L. Hayes and K.K. Wang, Cell. Mol. Biol. Lett., 11, 12 (2006); doi:10.2478/s11658-006-0002-x.
  18. 18 P.P. Monnier, A. Sierra, J.M. Schwab, S. Henke-Fahle and B.K. Mueller, Mol. Cell. Neurosci., 22, 319 (2003); doi:10.1016/S1044-7431(02)00035-0.
  19. S.- Satoh, T. Utsunomiya, K. Tsurui, T. Kobayashi, I. Ikegaki, Y. Sasaki and T. Asano, Life Sci., 69, 1441 (2001); doi:10.1016/S0024-3205(01)01229-2.
  20. M. Iwakubo, A. Takami, Y. Okada, T. Kawata, Y. Tagami, H. Ohashi, M. Sato, T. Sugiyama, K. Fukushima and H. Iijima, Bioorg. Med. Chem., 15, 350 (2007); doi:10.1016/j.bmc.2006.09.052.
  21. T. Asano, I. Ikegaki, S. Satoh, Y. Suzuki, M. Shibuya, M. Takayasu and H. Hidaka, J. Pharmacol. Exp. Ther., 241, 1033 (1987).
  22. M. Iwakubo, A. Takami, Y. Okada, T. Kawata, Y. Tagami, M. Sato, T. Sugiyama, K. Fukushima, S. Taya, M. Amano, K. Kaibuchi and H. Iijima, Bioorg. Med. Chem., 15, 1022 (2007); doi:10.1016/j.bmc.2006.10.028.
  23. B.S.P. Takekazu Kubo, B.S.P. Katsuhiko Hata, B.S.P. Atsushi Yamaguchi and B.S.P. Toshihide Yamashita, Curr. Pharm. Des., 13, 2493 (2007); doi:10.2174/138161207781368657.
  24. P.P. Monnier, A. Sierra, J.M. Schwab, S. Henke-Fahle and B.K. Mueller, Mol. Cell. Neurosci., 22, 319 (2003); doi:10.1016/S1044-7431(02)00035-0.
  25. Y. Hou, L. Zhou, Q.D. Yang, X.P. Du, M. Li, M. Yuan and Z.W. Zhou, Neuroscience, 200, 120 (2012); doi:10.1016/j.neuroscience.2011.10.030.
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