Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Synthesis of a Novel Series of Imidazo[1,2-α]pyridines as Acyl-CoA: Cholesterol Acyltransferase (ACAT) Inhibitors

  • Jin, Ying-Lan (Korea Research Institute of Biosciences and Biotechnology (KRIBB)) ;
  • Rho, Mun-Chual (Korea Research Institute of Biosciences and Biotechnology (KRIBB)) ;
  • Gajulapati, Kondaji (School of Life Sciences and Biotechnology, Korea University) ;
  • Jung, Hwa-Young (School of Life Sciences and Biotechnology, Korea University) ;
  • Boovanahalli, Shanthaveerappa K. (Korea Research Institute of Biosciences and Biotechnology (KRIBB)) ;
  • Lee, Jee-Hyun (College of Pharmacy, Chungnam National University) ;
  • Song, Gyu-Yong (College of Pharmacy, Chungnam National University) ;
  • Choi, Jung-Ho (Korea Research Institute of Biosciences and Biotechnology (KRIBB)) ;
  • Kim, Young-Kook (Korea Research Institute of Biosciences and Biotechnology (KRIBB)) ;
  • Lee, Kyeong (Korea Research Institute of Biosciences and Biotechnology (KRIBB)) ;
  • Choi, Yong-Seok (School of Life Sciences and Biotechnology, Korea University)
  • Published : 2009.06.20
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Abstract

A novel series of imidazo[1,2-$\alpha$]pyridines was designed, synthesized, and tested for their ability to inhibit acyl- CoA:cholesterol acyltransferase. Preliminary lead optimization efforts resulted in the identification of ACAT inhibitors represented by analogues 5b, 5c, 6a, 6c, 7b, and 7c. The ACAT inhibitory activity of these compounds was further established by potent inhibition of cholesteryl ester formation in HepG2 cells by a representative analogue 7b.

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References

  1. Goodman, D. S. Physiol. Rev. 1965, 45, 747.
  2. Chang, T.;Doolittle, G. M. In The Enzymes, 3rd ed.; Boyer, P. D., Ed.; Academic Press: New York, 1985; Vol. 16, p 523.
  3. Largis, E. E.; Wang, C. H.; DeVries, V. G.; Schaffer, S. A. J. Lipid Res. 1989, 30, 681.
  4. Suckling, K. E.; Stange, E. F. J. Lipid Res. 1985, 26, 647.
  5. Heider, J. G.; Pickens, C. E.; Kelly, L. A. J. Lipid Res. 1983, 24, 1127.
  6. Giovannoni, M. P.; Dal Piaz, V.; Vergelli, C.; Barlocco, D. Mini-Rev. Med. Chem. 2003, 3, 576. https://doi.org/10.2174/1389557033487890
  7. Matsuda, K. Med. Res. Rev. 1994, 14, 271. https://doi.org/10.1002/med.2610140302
  8. McCarthy, P. A. Med. Res. Rev. 1993, 13,139. https://doi.org/10.1002/med.2610130203
  9. Ken-Ichiro, K.; Tatsuki, S.; Takumi, T.; Tsutomu, M.; Keiko, T.; Mikio, O.; Hirofumi, T.; Hisao, Y. J. Med. Chem. 1995, 38, 3174. https://doi.org/10.1021/jm00016a021
  10. Ken-Ichiro, K.; Tatsuki, S.; Takumi, T.; Toru, M.;Kenzo, W.; Hiroko, T.;Tsutomu, M.; Keiko, T.; Mikio, O.;Hirofumi, T.; Hisao, Y. J. Med. Chem. 1996, 39, 1262. https://doi.org/10.1021/jm950828+
  11. Akira, T.; Takeshi, T.; Hiroyuki, H.; Yuri, S.; Noriko, I.; Masae, S.;Hisashi, T.; Hirokazu, T. Bioorg. Med. Chem. 1998, 6, 15. https://doi.org/10.1016/S0968-0896(97)10009-8
  12. Jeong, T. S.; Kim, K. S.; Yu, H.; Kim, M. J.; Cho, K. H.; Choi, Y.K.; Kim, H. C.; Park, H. Y.; Lee, W. S. Bioorg. Med. Chem. 2005, 15, 385. https://doi.org/10.1016/j.bmcl.2004.10.066
  13. Naoto, M.; Tetsuya, K.; Mina, F.; Yasuji, S.; Koji, M. Bioorg. Med. Chem. Lett. 1999, 9, 2039. https://doi.org/10.1016/S0960-894X(99)00330-3
  14. Lee, S.; Han, J. M.;Kim, H.; Kim, E.; Jeong, T. S.; Lee, W. S.; Cho, K. H. Bioorg. Med. Chem. Lett. 2004, 18, 4677.
  15. Xu, M. Z.; Lee, W. S.; Kim, M. J.; Park, D.-S.; Yu, H.; Tian, G.-R.; Jeong, T. S.; Park, H. Y. Bioorg. Med. Chem. Lett. 2004, 14, 4277. https://doi.org/10.1016/j.bmcl.2004.05.086
  16. Lee, W. S.; Lee, D.W.; Baek, Y. I.; An, S. J.; Cho, K. H.; Choi, Y. K.; Kim, H. C.; Park, H. Y.; Bae, K. H.; Jeong, T. S. Bioorg. Med. Chem. Lett. 2004, 14, 3109. https://doi.org/10.1016/j.bmcl.2004.04.023
  17. Jeong, T. S.; Kim, K. S.; An, S. J.; Cho, K. H.;Lee, S.; Lee, W. S. Bioorg. Med. Chem. Lett. 2004, 14, 2715. https://doi.org/10.1016/j.bmcl.2004.03.079
  18. Kwon, B. M.; Kim, M. K.; Baek, N. I.; Kim, D. S.; Park, J. D.;Kim, Y. K.; Lee, H.; Kim, S. I. Bioorg. Med. Chem. Lett. 1999, 9, 1375. https://doi.org/10.1016/S0960-894X(99)00208-5
  19. Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.;Andrei, G.; Chavignon, O.; Teulade, J.-C.; Kerbal, A.; Essassi, E. M.; Debouzy, J.-C.; Witvrouw, M.; Blache, Y.; Balzarini, J.;De Clercq, E.; Chapat, J.-P. J. Med. Chem. 1996, 39, 2856. https://doi.org/10.1021/jm9507901
  20. Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli, P.; Biancotti, A.; Gamba, A.; Murmann, W. J. Med. Chem. 1965, 8, 305. https://doi.org/10.1021/jm00327a007
  21. Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.;Imai, K.; Inamura, N.; Asano, M.; Hatori, C.; Katayama, A.;Oku, T.; Tanaka, T. J. Med. Chem. 1998, 41, 564. https://doi.org/10.1021/jm970591c
  22. Trapani, G.;Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.;Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42, 3934. https://doi.org/10.1021/jm991035g
  23. Katritzky, A. R.; Xu, Y.-J.; Tu, H. J. Org. Chem. 2003, 68, 4935 https://doi.org/10.1021/jo026797p
  24. Mosby, W. L. In Heterocyclic Systems with Bridgehead Nitrogen Atoms; Mosby, W. L., Ed.; Wiley: New York, 1961; Part I, p 460 and Part II, p 802.
  25. Blewitt, W. L. In Special Topics in Heterocyclic Chemistry; Weissberger, A.; Taylor, E. C., Eds.; Wiley: New York, 1977; p 117.
  26. Sablayrolles, C.; Cros, G. H.;Milhavet, J. C.; Rechenq, E.; Chapat, J.-P.; Boucard, M.;Serrano, J. J.; McNeill, J. H. J. Med. Chem. 1984, 27, 206. https://doi.org/10.1021/jm00368a018
  27. Spitzer, W. A.; Victor, F.; Pollock, D. G.; Hayers, J. S. J. Med. Chem. 1988, 31, 1590. https://doi.org/10.1021/jm00403a018
  28. Rho, M.-C.; Lee, S. W.; Park, H. R.; Choi, J. H.; Kang, J. Y.;Kim, K.; Lee, H. S.; Kim, Y. K. Phytochemistry 2007, 68, 899. https://doi.org/10.1016/j.phytochem.2006.11.025

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