T. Noguchi-Yachide et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3957–3961
11. Hashimoto, Y. Bioorg. Med. Chem. 2002, 10, 461.
3961
In conclusion, we discovered LXR antagonists [CP4P
(5), PPS-33 (6), and their derivatives] among our a-glu-
cosidase competitive inhibitors derived from thalido-
mide. Based on a consideration of our findings and
reported information, novel LXR antagonists with a
20-substituted phenylphthalimide skeleton, PP60 (15),
and PP2P (16), were designed and synthesized. Further
investigation of the structure–activity relationships,
development of superior LXR ligands, and further
applications of phenylphthalimide-related structures as
glucose mimics are in progress.
12. Hashimoto, Y.; Tanatani, A.; Nagasawa, K.; Miyachi, H.
Drugs Future 2004, 29, 383.
13. Sou, S.; Mayumi, S.; Takahashi, H.; Yamasaki, R.;
Kadoya, S.; Sodeoka, M.; Hashimoto, Y. Bioorg. Med.
Chem. 2000, 10, 1081.
14. Takahashi, H.; Sou, S.; Yamasaki, R.; Sodeoka, M.;
Hashimoto, Y. Chem. Pharm. Bull. 2000, 48, 1494.
15. Sou, S.; Takahashi, H.; Yamasaki, R.; Kagechika, H.;
Endo, Y.; Hashimoto, Y. Chem. Pharm. Bull. 2001, 49,
791.
16. Shimazawa, R.; Takayama, H.; Kato, F.; Kato, M.;
Hashimoto, Y. Bioorg. Med. Chem. Lett. 1999, 9,
559.
17. Makishima, M.; Lu, T. T.; Xie, W.; Whitfield, G. K.;
Domoto, H.; Evans, R. M.; Haussler, M. R.; Mangels-
dorf, D. J. Science 2002, 296, 1313.
18. Makishima, M.; Okamoto, A. Y.; Repa, J. J.; Tu,
H.; Learned, R. M.; Luk, A.; Hull, M. V.; Lustig,
K. D.; Mangelsdorf, D. J.; Shan, B. Science 1999,
284, 1362.
Acknowledgments
The work described in this paper was partially sup-
ported by Grants-in-Aid for Scientific Research from
The Ministry of Education, Culture, Sports, Science
and Technology, Japan, and the Japan Society for the
Promotion of Science. The authors thank Mr. Jun-ichi
Kasuga (IMCB, Univ. Tokyo) for his technical support
and helpful discussions.
19. Kasuga, J.; Makishima, M.; Hashimoto, Y.; Miyachi, H.
Bioorg. Med. Chem. Lett. 2006, 16, 554.
20. 5CP4P (12): mp. 77.0–77.5 °C. 1H-NMR (500 MHz,
CDCl3):
d 7.81 (1H, d, J = 1.8 Hz), 7.77 (1H, d,
J = 8.1 Hz), 7.67 (1H, dd, J = 8.1, 1.8 Hz), 7.26 (2H, d,
J = 7.0 Hz), 7.18 (1H, t, J = 7.0 Hz), 7.16 (2H, d,
J = 7.0 Hz), 3.70 (2H, t, J = 7.3 Hz), 2.65 (2H, t,
J = 7.3 Hz), 1.69 (4H, m). Anal. Calcd for C18H16NO2Cl:
C, 68.90; H, 5.14; N, 4.47. Found: C, 68.66; H, 5.12; N,
4.40.
References and notes
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24. PP60 (15): Mp. 65.3–66.3 °C. 1H-NMR (500 MHz,
CDCl3): d 7.95–7.98 (2H, m), 7.78–7.83 (2H, m), 7.41
(1H, dt, J = 1.22, 7.63 Hz), 7.39 (1H, dd, J = 7.33,
2.44 Hz), 7.33 (1H, dt, J = 2.44, 7.33 Hz), 7.17 (1H, dd,
J = 7.63, 1.22 Hz), 2.48 (2H, t, J = 7.94 Hz), 1.49–1.54
(2H, m), 1.23–1.27 (6H, m), 0.77 (3 H, t, J = 6.78 Hz).
Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56.
Found: C, 77.95; H, 6.98; N, 4.65.
25. PP2P (16): Mp. 90.8–91.2 °C. 1H-NMR (500 MHz,
CDCl3): d 7.94–7.98 (2H, m), 7.78–7.82 (2H, m), 7.40
(1H, dt, J = 1.52, 7.48 Hz), 7.33–7.37 (2H, m), 7.16–
7.22 (3H, m), 7.10–7.15 (1H, m), 7.04–7.08 (2H, m),
2.78–2.89 (4 H, m). Anal. Calcd for C22H17NO2: C,
80.71; H, 5.23; N, 4.28. Found: C, 80.85; H, 5.36; N,
4.20.