Inhibitors of the tyrosine kinase EphB4. Part 3: Identification of non-benzodioxole-based kinase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 21, 2010, Pages 6242-6245

  Bardelle, Catherine ^a   Barlaam, Bernard ^a   Brooks, Nigel ^a   Coleman, Tanya ^a   Cross, Darren ^a   Ducray, Richard ^a   Green, Isabelle ^a   Brempt, Christine Lambert Van Der ^a   Olivier, Annie ^a   Read, Jon ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

bis Anilinopyrimidine; EphB4 kinase inhibitor

Indexed keywords

ANTINEOPLASTIC AGENT; BENZIMIDAZOLE; CYTOCHROME P450; EPHRIN RECEPTOR B4; INDAZOLE DERIVATIVE; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR;

ALKYLATION; ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; DOG; DRUG BLOOD LEVEL; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; FEMALE; IN VIVO STUDY; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; BENZODIOXOLES; CHO CELLS; CRICETINAE; CRICETULUS; CRYSTALLOGRAPHY, X-RAY; DOGS; FEMALE; MALE; MICE; MICE, NUDE; MODELS, MOLECULAR; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; RATS; RATS, WISTAR; RECEPTOR, EPHB4; SRC-FAMILY KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 77957857898     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.08.100     Document Type: Article

References (33)

1. K. Kullander, and R. Klein Nat. Rev. Mol Cell. Biol. 3 2002 475
2. N. Cheng, D.M. Brantley, and J. Chen Cytokine Growth Factor Rev. 13 2002 75
3. J. Zhang, and S.E. Hughes J. Pathol. 208 2006 453
4. M. Héroult, F. Schnaffer, and H.G. Augustin Exp. Cell Res. 312 2006 642
5. D. Brandley-Sieders, S. Schmidt, M. Parker, and J. Chen Curr. Pharm. Des. 10 2004 3431
6. E.B. Pasquale Nature Rev. Cancer 10 2010 165
7. G. Xia, S.R. Kumar, R. Masood, S. Zhu, R. Reddy, V. Krasnoperov, D.I. Quinn, S.M. Henshall, R.L. Sutherland, J.K. Pinski, S. Daneshmand, M. Buscarini, J.P. Stein, C. Zhong, D. Broek, P. Roy-Burman, and P.S. Gill Cancer Res. 65 2005 4623
8. G. Martiny-Baron, T. Korff, F. Schaffner, N. Esser, S. Eggstein, D. Marmé, and H.G. Augustin Neoplasia 6 2004 248
9. N. Kertesz, V. Krasnoperov, R. Reddy, L. Leshanski, S.R. Kumar, S. Zozulya, and P.S. Gill Blood 107 2006 2330
10. S.S. Gerety, H.U. Wang, Z.-F. Chen, and D. Anderson J. Mol. Cell 4 1999 403
11. H.U. Wang, Z.-F. Chen, and D.J. Anderson Cell 93 1998 741
12. R. Erber, U. Eichelsbacher, V. Powajbo, T. Korn, V. Djonov, J. Lin, H.-P. Hammes, R. Grobholz, A. Ullrich, and P. Vajkoczy EMBO J. 25 2006 628
13. S.R. Kumar, J. Singh, G. Xia, V. Krasnoperov, L. Hassanieh, E.J. Ley, J. Scehnet, N.G. Kumar, D. Hawes, M.F. Press, F.A. Weaver, and P.S. Gill Am. J. Pathol. 169 2006 279
14. N.K. Noren, G. Foss, C.A. Hauser, and E.B. Pasquale Nat. Cell Biol. 8 2006 815
15. N.K. Noren, and E.B. Pasquale Cancer Res. 67 2007 3994
16. E.B. Pasquale Cell 133 2008 38
17. C. Bardelle, D. Cross, S. Davenport, J.G. Kettle, E.J. Ko, A.G. Leach, A. Mortlock, J. Read, N.J. Roberts, P. Robins, and E.J. Williams Bioorg. Med. Chem. Lett. 18 2008 2776
18. C. Bardelle, T. Coleman, D. Cross, S. Davenport, J.G. Kettle, E.J. Ko, A.G. Leach, A. Mortlock, J. Read, N.J. Roberts, P. Robins, and E.J. Williams Bioorg. Med. Chem. Lett. 18 2008 5717
19. A.S. Kalgutkar, I. Gardner, R.S. Obach, C.L. Shaffer, E. Callegari, K.R. Henne, A.E. Mutlib, D.K. Dalvie, J.S. Lee, Y. Nakai, J.P. O'Donnell, J. Boer, and S.P. Harriman Current Drug Metab. 6 2005 161
20. M. Murray Current Drug Metab. 1 2000 67 CYP Time dependant inhibition (TDI) was evaluated by preincubating the compound (10 μM) with HLM (human liver microsomes) for 30 min in the presence versus absence of NADPH, followed by incubation with a specific CYP substrate with NADPH. Compound 1 gave 26% TDI against CYP3A4 and 2 gave 42% and 40% TDI resp. against CYP3A4 and 2C9. Compound 20 showed 62% TDI against CYP3A4.
21. For detailed conditions for the synthesis of compounds 3-31 and description of biological assays, see: Kettle, J. G.; Read, J.; Leach, A.; Barlaam, B. C.; Ducray, R.; Lambert-Van Der Brempt, C. M. P. PCT Int. Appl. WO2007085833. Protecting groups for the indazolyl endocyclic nitrogen were used for compounds 19, 20, 22, 24, 26 (benzyl) or 29-31 (4-methoxybenzyl). For 7 and 8, the aminobenzoxazole was introduced as the 2-Boc-NH 6-aminophenol and the 2-Boc-NH 3-aminophenol. Removal of the Boc protecting group with TFA and formation of the benzoxazole ring by treatment with trimethyl orthoformate with p-toluenesulfonic acid gave the expected benzoxazoles.
22. D.D. Davey, M. Adler, D. Arnaiz, K. Eagen, S. Erickson, W. Guilford, M. Kenrick, M.M. Morrissey, M. Ohlmeyer, G. Pan, V.M. Paradkar, J. Parkinson, M. Polokoff, K. Saionz, C. Santos, B. Subramanyam, R. Vergona, R.G. Wei, M. Whitlow, B. Ye, Z. Zhao, J.J. Devlin, and G. Phillips J. Med. Chem. 50 2007 1146
23. For a previous report of analogous regioselective reactions, see: Ito, S.; Sumi, K.; Masuda, K.; Kojima, Y.; Sawai, N. Jpn. Kokai Tokkyo Koho JP62106084.
24. For description of the EphB4 enzyme assay (using acoustic dispensing), see: Barlaam, B. C.; Ducray, R. PCT Int. Appl. WO2008132505.
25. 24 and structure factors for the EphB4 complexes with compounds 9 have been deposited in the Protein Data Bank (2xf9 ) together with structure factors and detailed experimental conditions.
26. P.A. Ple, T.P. Green, L.F. Hennequin, J. Curwen, M. Fennell, J. Allen, C. Lambert-van der Brempt, and G. Costello J. Med. Chem. 47 2004 871
27. P. Bamborough, R.M. Angell, I. Bhamra, D. Brown, J. Bull, J.A. Christopher, A.W.J. Cooper, L.H. Fazal, I. Giordano, L. Hind, V.K. Patel, L.E. Ranshaw, M.J. Sims, P.A. Skone, K.J. Smith, E. Vickerstaff, and M. Washington Bioorg. Med. Chem. Lett. 17 2007 4363
28. W.L. DeLano The PyMOL Molecular Graphics System 2002 DeLano Scientific San Carlos, CA, USA http://www.pymol.org
29. CCP4 Acta Crystallogr., Sect. D D50 1994 760
30. Coot, P. Emsley, and K. Cowtan Acta Crystallogr., Sect. D 60 2004 2126
31. AFITT, Openeye.
32. Refmac version 5.1.17: G.N. Murshudov, A.A. Vagin, and E.J. Dodson Acta Crystallogr., Sect. D 53 1997 240
33. 2, respectively.