Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 9, 2009, Pages 2595-2598

  Feng, Song ^a   Yang, Minmin ^a   Zhang, Zhenshan ^a   Wang, Zhanguo ^a   Hong, Di ^a   Richter, Hans ^b   Benson, Gregory Martin ^b   Bleicher, Konrad ^b   Grether, Uwe ^b   Martin, Rainer E ^b   Plancher, Jean Marc ^b   Kuhn, Bernd ^b   Rudolph, Markus Georg ^b   Chen, Li ^a  

^a Roche China Ltd   (China)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Agonist; Farnesoid X receptor (FXR); Isoxazole; N Oxide pyridine

Indexed keywords

3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID; 3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID DERIVATIVE; FARNESOID X RECEPTOR; FARNESOID X RECEPTOR AGONIST; HYDROGEN; ISOXAZOLE DERIVATIVE; OXIDE; PYRIDINE; PYRIDINE DERIVATIVE; SERINE; TYROSINE; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CRYSTAL STRUCTURE; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; HYDROGEN BOND;

BINDING SITES; CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HUMANS; HYDROGEN BONDING; ISOXAZOLES; LIGANDS; MODELS, CHEMICAL; PROTEIN BINDING; RECEPTORS, CYTOPLASMIC AND NUCLEAR; SERINE; TYROSINE;

EID: 64249153603     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.03.008     Document Type: Article

References (32)

1. Goodwin B., Jones S.A., Price R.R., Watson M.A., McKee D.D., Moore L.B., Galardi C., Wilson J.G., Lewis M.C., Roth M.E., Maloney P.R., Willson T.M., and Kliewer S.A. Mol. Cell. 6 (2000) 517
2. Makishima M., Okamoto A.Y., Repa J.J., Tu H., Learned R.M., Luk A., Hull M.V., Lustig K.D., Mangelsdorf D.J., and Shan B. Science 274 (1999) 1362
3. Parks D.J., Blanchard S.G., Bledsoe R.K., Chandra G., Consler T.G., Kliewer S.A., Stimmel J.B., Willson T.M., Zavacki A.M., Moore D.D., and Lehmann J.M. Science 274 (1999) 1365
4. Wang H., Chen J., Hollister K., Sowers L.C., and Forman B.M. Mol. Cell. 3 (1999) 543
5. Lu T.T., Makishima M., Repa J.J., Schoonjans K., Kerr T.A., Auwerx J., and Mangelsdorf D.J. Mol. Cell. 6 (2000) 507
6. Wang L., Lee Y.-K., Bundman D., Han Y., Thevananther S., Kim C.-S., Chua S.S., Wei P., Heyman R.A., Karin M., and Moore D.D. Dev. Cell. 2 (2002) 721
7. Ananthanarayanan M., Balasubramanian N., Makishima M., Mangelsdorf D.J., and Suchy F.J. J. Biol. Chem. 276 (2001) 27857
8. Cariou B., Van H.K., Duran-Sandoval D., Van Dijk T.H., Grefhorst A., Abdelkarim M., Caron S., Torpier G., Fruchart J.-C., Gonzalez F.J., Kuipers F., and Staels B. J. Biol. Chem. 271 (2006) 11039
9. Watanabe M., Houten S.M., Wang L., Moschetta A., Mangelsdorf D.J., Heyman R.A., Moore D.D., and Auwerx J. J. Clin. Invest. 113 (2004) 1408
10. Zhang Y., Lee F.Y., Barrera G., Lee H., Vales C., Gonzalez F.J., Willson T.M., and Edwards P.A. Proc. Natl. Acad. Sci. U.S.A. 103 (2006) 1006
11. Maloney P.R., Parks D.J., Haffner C.D., Fivush A.M., Chandra G., Plunket K.D., Creech K.L., Moore L.B., Wilson J.G., Lewis M.C., Jones S.A., and Willson T.M. J. Med. Chem. 43 (2000) 2971
12. Trends Biochem. Sci. 31 (2006) 572
13. Kalaany N.Y., and Mangelsdorf D.J. Annu. Rev. Physiol. 68 (2006) 159
14. Cariou B., and Staels B. Trends Pharmacol. Sci. 27 (2007) 236
15. Fujino T., Une M., Imanaka T., Inoue K., and Nishimaki-Mogami T. J. Lipid Res. 45 (2004) 132
16. Pellicciari R., Fiorucci S., Camaioni E., Clerici C., Costantino G., Maloney P.R., Morelli A., Parks D.J., and Willson T.M. J. Med. Chem. 45 (2002) 3569
17. Nicolaou K.C., Evans R.M., Roecker A.J., Hughes R., Downes M., and Pfefferkorn J.A. Org. Biomol. Chem. 1 (2003) 908
18. Dussault I., Beard R., Lin M., Hollister K., Chen J., Xiao J.H., Chandraratna R., and Forman B.M. J. Biol. Chem. 278 (2003) 7027
19. Love J.D., Gooch J.T., Benko S., Li C., Nagy L., Chatterjee V.K., Evans R.M., and Schwabe J.W. J. Biol. Chem. 277 (2002) 11385
20. Soisson S.M., Parthasarathy G., Adams A.D., Sahoo S., Sitlani A., Sparrow C., Cui J., and Becker J.W. Proc. Natl. Acad. Sci. U.S.A. 105 (2008) 5337
21. Mahaney, P.E.; Harnish, D.C.; Abou-Gharbia, M.A.; et al. Abstracts of Papers 235th ACS National Meeting, New Orleans, LA, 2008, Abst MEDI 181.
22. www.clinictrials.gov
23. Bell, M. G.; Genin, M. J.; Lander, P. A.; Stelzer, L. S.; Doti, R. A.; Agejas-Chicharro, F. J.; Bueno Melendo, A. B.; Manninen, P. R.; Ochoada, J. M.; Shen, Q.; Warshawsky, A. M.; Ma, T.; Stites, R. E. Patent WO 2007092751, 2007.
24. Michael G.; Doti, R. A.; Genin, M. J.; Lander, P. A.; Ma, T.; Manninen, P. R.; Ochoada, J. M.; Qu, F.; Stelzer, L. S.; Stites, R. E.; Warshawsky, A. M. Patent WO2007140183, 2007.
25. Bell, M. G.; Doti, R. A.; Dowling, M. S.; Genin, M. J.; Lander, P. A.; Ma, T.; Mantlo, N. B.; Ochoada, J. M.; Stelzer, L. S.; Stites, R. E.; Warshawsky, A. M. Patent WO2007140174, 2007.
26. Kremoser, C.; Deuschle, U.; Abel, U.; Schulz, A. Patent WO2008025539, 2008.
27. Navas F.; Spearing P. K. U.S. Patent 2008096921, 2008.
28. Crystallographic data for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 3FXV.
29. Akwabi-Ameyaw A., Bass J.Y., Caldwell R.D., Caravella J.A., Chen L., Creech K.L., Deaton D.N., Jones S.A., Kaldor I., Liu Y., Madauss K.P., Marr H.B., McFadyen R.B., Miller A.B., Navas III F., Parks D.J., Spearing P.K., Todd D., Williams S.P., and Wisely G.B. Bioorg. Med. Chem. Lett. 18 (2008) 4339
30. Masahiko K., Makoto M., Yuichi H., and Hiroyuki M. Bioorg. Med. Chem. 15 (2007) 2587
31. Nichols J.S., Parks D.J., Consler T.G., and Blanchard S.G. Anal. Biochem. 257 (1998) 112
32. 3): 8.23 (d, J = 8.0 Hz), 7.92 (s, 1H), 7.40 (d, J = 10.0 Hz), 7.27 (m,1H), 7.22 (m, 2H), 6.71 (m, 3H), 4.95 (d, J = 11.6 Hz, 1H), 4.76 (d, J = 11.6 Hz, 1H), 3.89 (s, 3H), 3.38 (m, 4H), 2.27 (s, 3H), 1.49 (m, 6H).