Conversion of systemically-distributed triazole-based stearoyl-CoA desaturase (SCD) uHTS hits into liver-targeted SCD inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 21, 2011, Pages 6505-6509

  Leclerc, Jean Philippe ^a   Falgueyret, Jean Pierre ^a   Girardin, Mélina ^a   Guay, Jocelyne ^a   Guiral, Sébastien ^a   Huang, Zheng ^a   Li, Chun Sing ^a   Oballa, Renata ^a   Ramtohul, Yeeman K ^a   Skorey, Kathryn ^a   Tawa, Paul ^a   Wang, Hao ^a   Zhang, Lei ^a  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

Author keywords

Liver targeted; MK 8245; SCD inhibitors; Stearoyl CoA desaturase inhibitors; Triazoles

Indexed keywords

ACYL COENZYME A DESATURASE; ENZYME INHIBITOR; MF 152; MF 438; MK 8245; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CHRONIC TOXICITY; DRUG ACTIVITY; DRUG POTENCY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IC 50; LIVER CELL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

EID: 80054792773     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.08.073     Document Type: Article

References (40)

1. (a) Dobrzyn, P.; Dobrzyn, A. Expert Opin. Ther. Patents 2010, 20, 849
2. (b) Liu, G. Expert Opin. Ther. Patents 2009, 19, 1169;
3. (c) Kopelman, P. G. Nature 2000, 404,635.
4. Enoch, H. G.; Catala, A.; Strittmatter, P. J. Biol. Chem. 1976, 251, 5095.
5. Ntambi, J. M. Prog. Lipid Res. 1995, 34, 139.
6. (a) Jiang, G.; Li, Z.; Liu, F.; Ellsworth, K.; Dallas-Yang, Q.; Wu, M.; Ronan, J.; Esau, C.; Murphy, C.; Szalkowski, D.; Bergeron, R.; Doebber, T.; Zhang, B. B. J. Clin. Invest. 2005, 115, 1030
7. (b) Miyazaki, M.; Flowers, M. T.; Sampath, H.; Chu, K.; Otzelberger, C.; Liu, X.; Ntambi, J. M. Cell Metab. 2007, 6, 484
8. (c) Savransky, V.; Jun, J.; Li, J.; Nanayakkara, A.; Fonti, S.; Moser, A. B.; Steele, K. E.; Schweitzer, M. A.; Patil, S. P.; Bhanot, S.; Schwartz, A. R.; Polotsky, V. Y. Circ. Res. 2008, 103, 1173.
9. (a) Dobrzyn, A.; Ntambi, J. M. Prostaglandins Leukot. Essent. Fatty Acids 2005, 73, 35
10. (b) Dobrzyn, A.; Ntambi, J. M. Obes. Rev. 2005, 6, 169.
11. Li, C. S.; Belair, L.; Guay, J.; Murgasva, R.; Sturkenboom, W.; Ramtohul, Y. K.; Zhang, L.; Huang, Z. Bioorg. Med. Chem. Lett. 2009, 19, 5214.
12. Leger, S.; Black, C.; Deschenes, D.; Dolman, S.; Falgueyret, J.-P.; Gagnon, M.; Guiral, S.; Huang, Z.; Guay, J.; Leblanc, Y.; Li, C.-S.; Masse, F.; Oballa, R.; Zhang, L. Bioorg. Med. Chem. Lett. 2010, 20, 499.
13. (a) Xin, Z.; Zhao, H.; Serby, M. D.; Liu, B.; Liu, M.; Szczepankiewicz, B. G.; Nelson, L. T.; Smith, H. T.; Suhar, T. S.; Janis, R. S.; Cao, N.; Camp, H. S.; Collins, C. A.; Sham, H. L.; Surowy, T. K.; Liu, G. Bioorg. Med. Chem. Lett. 2008, 18, 4298
14. (b) Winther, M. D. 2nd Annual Drug Development for Diabetes and Obesity, London, UK, Jan 17-18, 2008.
15. (c) 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.; Zablocki, J. Bioorg. Med. Chem. Lett. 2009, 19, 3050
16. (d) 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, 4159
17. (e) Ramtohul, Y. K.; Black, C.; Chan, C.-C.; Crane, S.; Guay, J.; Guiral, S.; Huang, Z.; Oballa, R.; Xu, L.-J.; Zhang, L.; Li, C. S. Bioorg. Med. Chem. Lett. 2010, 12, 23
18. (f) Powell, D. A.; Ramtohul, Y. K.; Lebrun, M.-E.; Oballa, R.; Falgueyret, J.-P.; Guiral, S.; Huang, Z.; Skorey, K.; Tawa, P.; Zhang, L. Bioorg. Med. Chem. Lett. 2010, 20, 6366
19. ACS 240th, Boston, 2010.
20. (h) Isabel, E.; Powell, D. A.; Black, C.; Chan, C.-C.; Crane, S.; Gordon, R.; Guay, J.; Guiral, S.; Huang, Z.; Robichaud, J.; Skorey, K.; Tawa, P.; Xu, L.; Zhang, L.; Oballa, R. Bioorg. Med. Chem. Lett. 2011, 21, 479;
21. (i) Atkinson, K. A.; Beretta, E. E.; Brown, J. A.; Castrodad, M.; Chen, Y.; Cosgrove, J. M.; Du, P.; Litchfield, J.; Makowski, M.; Martin, K.; McLellan, T. J.; Neagu, C.; Perry, D. A.; Piotrowski, D. W.; Steppan, C. M.; Trilles, R. Bioorg. Med. Chem. Lett. 2011, 21, 1621.
22. (a) Five initial applications from Xenon (WO2005/011653 to WO 2005/011657) were published on February 10, 2005. WO2008/074835 and WO2009/106991 were also published in 2008 and 2009 respectively. Representative one: 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.; Winther, M. D.; Zhang, Z. WO2005/011655.;
23. (b) Xenon/Novartis patent: Dales, N.; Zhang, Z. WO2008/024390.;
24. (c) Three patents from GSK in 2009: WO2009/016216, WO2009/060053 and WO2009/060054 Representative one: Bouillot, A. M. J.; Laroze, A.; Trottet, L. WO2009/060053.
25. 6 compounds were tested and 12109 were found to give>35% inhibition at 9 μM. After confirmation of the potency (triplicate of the binding assay), compounds were filtered, clustered and then tested in a rat microsomal assay using a 3 point titration. Finally, the best compounds were retested in the same rat assay using a 10 point titration curve. For more details see Skorey, K. and co-worker, J. Biomol. Screen. 2011, 16, 506.
26. For rat microsomal assay conditions, see: Li, C. S.; Ramtohul, Y.; Huang, Z.; Lachance, N. WO2006/130986.
27. Oballa, R. M.; Belair, L.; Black, C.; Bleasby, K.; Chan, C. C.; Desroches, C.; Du, X.; Gordon, R.; Guay, J.; Guiral, S.; Hafey, M. J.; Hamelin, E.; Huang, Z.; Kennedy, B.; Lachance, N.; Landry, F.; Li, C. S.; Mancini, J.; Normandin, D.; Pocai, A.; Powell, D.; Ramtohul, Y.; Skorey, K.; Sturkenboom, W.; Styhler, A.; Waddleton, D.; Wang, H.; Wong, S.; Xu, L.; Zhang, L. J. Med. Chem. 2011, 54, 5082.
28. For a review on OATP transporters, see: Niemi, M. Pharmacogenomics 2007, 8, 787.
29. For detailed experimental procedures, see: Leclerc, J.-P.; Li, C. S.; Ramtohul, Y. K. WO 2010/025553.
30. For detailed experimental procedures on the synthesis of azide 10, see: Strassburg, R. W.; Gregg, R. A.; Walling, C. J. Am. Chem. Soc. 1947, 69, 2141.
31. 15N gHMBC and 1D NOESY.
32. For detailed experimental procedures on the synthesis of azides 11 and 12, see: (a) Blankespoor, L. R.; DeVries, T.; Hansen, E.; Kallemeyn, M. J.; Klooster, M. A.; Mulder, A. J.; Smart, P. R.; Vander Griend, A. D. J. Org. Chem. 2002, 67, 2677;
33. (b) Katzenellenbogen, A. J.; Robertson, D. W. J. Org. Chem. 1982, 47, 2387.
34. Unpublished results.
35. For detailed experimental procedures on acylchloride syntheses, see: (a) Thompson, A.; Regourd, J.; Al-Sheikh Ali, A. J. Med. Chem. 2007, 50, 1528;
36. (b) Shiraishi, M.; Kato, K.; Terao, S.; Ashida, Y.; Terashita, Z.-I.; Kito, G. J. Med. Chem. 1989, 32, 2214.
37. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
38. Intermediate 30 was obtained from the reaction of azide 9 with ethynyltri-Nbutyltin in benzene at 80°C for 5 h.
39. Zhang, L.; Ramtohul, Y.; Gagné, S.; Styhler, A.; Guay, J.; Huang, Z. J. Biomol. Screen. 2010, 15, 169.
40. 5050 values over HepG2 inhibition. Therefore, this can be use to evaluate the potential liver-targeted nature of a compound before performing pharmacokinetic studies.