Novel and potent inhibitors of stearoyl-CoA desaturase-1. Part I: Discovery of 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4151-4158

  Uto, Yoshikazu ^a   Ogata, Tsuneaki ^a   Harada, Jun ^a   Kiyotsuka, Yohei ^a   Ueno, Yuko ^a   Miyazawa, Yuriko ^a   Kurata, Hitoshi ^a   Deguchi, Tsuneo ^b   Watanabe, Nobuaki ^b   Takagi, Toshiyuki ^a   Wakimoto, Satoko ^a   Okuyama, Ryo ^a   Abe, Manabu ^a   Kurikawa, Nobuya ^a   Kawamura, Sayako ^a   Yamato, Michiko ^a   Osumi, Jun ^a  

^a DAIICHI SANKYO CO   (Japan)

^b Drug Metabolism and Pharmacokinetics Research Laboratories   (Japan)

Author keywords

SCD1 inhibitors; Thiazole

Indexed keywords

3 (2 HYDROXYETHOXY) 4 METHOXY N [5 (3 TRIFLUOROMETHYLBENZYL)THIAZOL 2 YL]BENZAMIDE; ACYL COENZYME A DESATURASE; ACYL COENZYME A DESATURASE 1; ENZYME INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; ARYLATION; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG MECHANISM; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; HUMAN; HYDROPHILICITY; IC 50; MALE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION;

ADMINISTRATION, ORAL; ANIMALS; AREA UNDER CURVE; BENZAMIDES; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MICE; MICE, INBRED C57BL; MODELS, CHEMICAL; STEAROYL-COA DESATURASE; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 67649962601     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.119     Document Type: Article

References (30)

1. Dobrzyn A., and Ntambi J.M. Obesity Rev. 6 (2005) 169
2. Ntambi J.M., and Miyazaki M. Curr. Opin. Lipidol. 14 (2003) 255
3. Miyazaki M., Jacobsen M.J., Man W.C., Cohen P., Asilmaz E., Friedman J.M., and Ntambi J.M. J. Biol. Chem. 278 (2003) 33904
4. Wang J., Yu L., Schmidt R.E., Su C., Huang X., Gould K., and Cao G. Biochem. Biophys. Res. Commun. 332 (2005) 735
5. Zhang L., Ge L., Parimoo S., Stenn K., and Prouty S.M. Biochem. J. 340 (1999) 255
6. Miyazaki M., Kim Y.-C., Gray-Keller M.P., Attie A.D., and Ntambi J.M. J. Biol. Chem. 275 (2000) 30132
7. Flowers M.T., and Ntambi J.M. Curr. Opin. Lipidol. 19 (2008) 248
8. Dobrzyn P., and Dobrzyn A. Drug Development Res. 67 (2006) 643
9. Attie A.D., Krauss R.M., Gray-Keller M.P., Brownlie A., Miyazaki M., Kastelein J.J., Lusis A.J., Stalenhoef A.F.H., Stoehr J.P., Hayden M.R., and Ntambi J.M. J. Lipid Res. 43 (2002) 1899
10. For the typical structures of Xenon's SCD-1 inhibitors, see: Abreo, M.; Chafeev, M.; Chakka, N.; Chowdhury, S.; Fu, J.-M.; Gschwend, H. W.; Holladay, M. W.; Hou, D.; Kamboj, R.; Kodumuru, V.; Li, W.; Liu, S.: Raina, V.; Sun, S.; Sun, S.; Sviridov, S.; Tu, C.; Winther, M. D.; Zhang, Z. WO2005011655A2, February 10, 2005.
11. Liu G., Lynch J.K., Freeman J., Liu B., Xin Z., Zhao H., Serby M.D., Kym P.R., Suhar T.S., Smith H.T., Cao N., Yang R., Janis R.S., Krauser J.A., Cepa S.P., Beno D.W.A., Sham H.L., Collins C.A., Surowy T.K., and Camp H.S. J. Med. Chem. 50 (2007) 3086
12. Zhao H., Serby M.D., Smith H.T., Cao N., Suhar T.S., Surowy T.K., Camp H.S., Collins C.A., Sham H.L., and Liu G. Bioorg. Med. Chem. Lett. 17 (2007) 3388
13. Xin Z., Zhao H., Serby M.D., Liu B., Liu M., Szczepankiewicz B.G., Nelson L.T.J., Smith H.T., Suhar T.S., Janis R.S., Cao N., Camp H.S., Collins C.A., Sham H.L., Surowy T.K., and Liu G. Bioorg. Med. Chem. Lett. 18 (2008) 4298
14. Recently, a group from CV Therapeutics reported 2-oxo-2H-quinoxalin-based SCD-1 inhibitors:. Koltun D.O., Parkhill E.Q., Vasilevich N.I., Glushkov A.I., Zilbershtein T.M., Ivanov A.V., Cole A.G., Henderson I., Zautke N.A., Brunn S.A., Mollova N., Leung K., Chisholm J.W., and Zablocki J. Bioorg. Med. Chem. Lett. 19 (2009) 2048
15. Koltun D.O., Vasilevich N.I., Parkhill E.Q., Glushkov A.I., Zilbershtein T.M., Mayboroda E.I., Boze M.A., Cole A.G., Henderson I., Zautke N.A., Brunn S.A., Chu N., Hao J., Mollova N., Leung K., Chisholm J.W., and Zablocki J. Bioorg. Med. Chem. Lett. 19 (2009) 3050
16. During the preparation of this manuscript, a group at Dainippon Sumitomo Pharmaceutical reported 4-aminoimidazole based SCD-1 inhibitors, which were derived from a hit compound structurally similar to 5a (Yamaguchi, H. The 27th Medicinal Chemistry Symposium, Osaka, Japan, November, 2008).
17. 1H NMR and mass spectroscopy.
18. Obushak N.D., Matiichuk V.S., Vasylyshin R.Y., and Ostapyuk Y.V. Russ. J. Org. Chem. 40 (2004) 383
19. Jeffery T. Tetrahedron Lett. 32 (1991) 2121
20. Halland N. J. Am. Chem. Soc. 126 (2004) 4790
21. 3):δ 9.84(1H, s), 7.49-7.39(4H, m), 3.02(2H, t, J = 7.4 Hz), 2.83(2H, t, J = 7.6 Hz).
22. +.
23. +.
24. +.
25. +.
26. +.
27. 14C] C18:4n - 3.
28. 14C] stearate.
29. 50.
30. Uto, Y.; Ogata, T.; Kiyotsuka, Y.; Miyazawa, Y. Ueno, Y.; Kurata, H.; Deguchi, T.; Yamada, M.; Watanabe, N.; Takagi, T.; Wakimoto, S.; Okuyama, R.; Konishi, M.; Kurikawa, N.; Kono, K.; Osumi, J. Bioorg. Med. Chem. Lett. 2009, 19, in press.