Inhibitors of VEGF receptors-1 and -2 based on the 2-((pyridin-4-yl)ethyl) pyridine template

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 7, 2006, Pages 1913-1919

  Kiselyov, Alexander S ^a   Semenova, Marina ^b   Semenov, Victor V ^c   Milligan, Daniel ^d  

^a CHEMDIV INC   (United States)

^b KOL TSOV INSTITUTE OF DEVELOPMENTAL BIOLOGY   (Russian Federation)

^c N D ZELINSKY INSTITUTE OF ORGANIC CHEMISTRY   (Russian Federation)

^d ELI LILLY AND COMPANY   (United States)

Author keywords

((Pyridin 4 yl)ethyl) pyridines; Angiogenesis; Dual kinase inhibitors; Receptor tyrosine kinase; Vascular endothelial growth factor receptor 2; VEGFR 1; VEGFR 2

Indexed keywords

1,3,4 OXADIAZOLE DERIVATIVE; ADENOSINE TRIPHOSPHATE; AROMATIC AMINE; FUNCTIONAL GROUP; PROTEIN KINASE; PYRIDINE DERIVATIVE; VANDETANIB; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; VATALANIB;

ARTICLE; CELL ASSAY; CELL MEMBRANE PERMEABILITY; CELL STRAIN CACO 2; CONTROLLED STUDY; DRUG ABSORPTION; DRUG ACTIVITY; DRUG DETERMINATION; DRUG IDENTIFICATION; DRUG PENETRATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SPECIFICITY; HUMAN; HUMAN CELL; IC 50; INTESTINE ABSORPTION; MONOLAYER CULTURE;

CACO-2 CELLS; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; PYRIDINES; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 33144483524     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.12.090     Document Type: Article

References (29)

1. W. Risau Nature 386 1997 671
2. D. Hanahan, and J. Folkman Cell 86 1996 353
3. J. Folkman, and M. Klagsburn Science 235 1987 442
4. J. Folkman J. Natl. Cancer Inst. 82 1991 4
5. E.S. Kerbel Carcinogenesis 21 2000 505
6. N. Ferrara, H.-P. Gerber, and J. LeCouter Nat. Med. 9 2003 669
7. P. Carmeliet, and R. Jain Nat. Med. 9 2003 653
8. T. Veikkola, M. Karkkainen, L. Claesson-Welsh, and K. Alitalo Cancer Res. 60 2000 203
9. M. Klagsbrun, and P. D'Amore Annu. Rev. Physiol. 53 1991 217
10. G. Neufeld, T. Cohen, S. Gengrinovitch, and Z. Poltorak FASEB J. 13 1999 9
11. I. Zachary Biochem. Soc. Trans. 31 2003 1171
12. M. Klagsbrun, and M.A. Moses Chem. Biol. 6 1999 R217
13. The anti-angiogenic antibody Avastin™ (Bevacizumab) has recently been approved to treat colorectal cancer see C. Culy Drugs Today 41 2005 23
14. The anti-angiogenic aptamer Macugen™ (Pegaptanib sodium) has recently been approved to treat neovascular age-related macular degeneration; see S.L. Fine, D.F. Martin, and P. Kirkpatrick Nat. Rev. Drug Disc. 4 2005 187
15. G. Bold, K.-H. Altmann, F. Jorg, M. Lang, P.W. Manley, P. Traxler, B. Wietfeld, J. Bruggen, E. Buchdunger, R. Cozens, S. Ferrari, F. Pascal, F. Hofmann, G. Martiny-Baron, J. Mestan, J. Rosel, M. Sills, D. Stover, F. Acemoglu, E. Boss, R. Emmenegger, L. Lasser, E. Masso, R. Roth, C. Schlachter, W. Vetterli, D. Wyss, and J.M. Wood J. Med. Chem. 43 2000 2310
16. L.F. Hennequin, E.S.E. Stokes, A.P. Thomas, C. Johnstone, P.A. Ple, D.J. Ogilvie, M. Dukes, S.R. Wedge, J. Kendrew, and J.O. Curwen J. Med. Chem. 45 2002 1300
17. S.R. Wedge, J. Kendrew, L.F. Hennequin, P.J. Valentine, S.T. Barry, S.R. Brave, N.R. Smith, N.H. James, M. Dukes, J.O. Curwen, R. Chester, J.A. Jackson, S.J. Boffey, L.L. Kilburn, S. Barnett, G.H.P. Richmond, P.F. Wadsworth, M. Walker, A.L. Bigley, S.T. Taylor, L. Cooper, S. Beck, J.M. Juergensmeier, and D.J. Ogilvie Cancer Res. 65 2005 4389
18. P.W. Manley, P. Furet, G. Bold, J. Brüggen, J. Mestan, T. Meyer, C. Schnell, and J. Wood J. Med. Chem. 45 2002 5697
19. P.W. Manley, G. Bold, G. Fendrich, P. Furet, J. Mestan, T. Meyer, B. Meyhack, A. Strauss, and J. Wood Cell. Mol. Biol. Lett. 8 2003 532
20. Altmann, K.-H.; Bold, G.; Furet, P.; Manley, P. W.; Wood, J. M.; Ferrari, S.; Hofmann, F.; Mestan, J.; Huth, A.; Krüger, M.; Seidelmann, D.; Menrad, A.; Haberey, M.; Thierauch, K.-H., U.S. Patent 6,878,720 B2, 2005.
21. E.L. Piatnitski, M. Duncton, R. Katoch-Rouse, D. Sherman, A.S. Kiselyov, D. Milligan, C. Balagtas, W. Wong, J. Kawakami, and J. Doody Bioorg. Med. Chem. Lett. 15 2005 4696
22. 5O: C, 61.31; H, 3.92; N, 17.02. Found: C, 61.15; H, 3.75, N, 16.86.
23. 2, 2 mM DTT, and 1 mg/ml BSA) containing 0.5 mmol pGAT-biotin and 3-4 ng KDR enzyme was added to each well. After 5-10 min preincubation, the kinase reaction was initiated by the addition of 10 μl of 10 μM ATP in the reaction buffer, after which the plate was incubated at room temperature for 45 min. The reaction was stopped by addition of 50 μl KF buffer (50 mM Hepes, pH 7.5 and 0.5 M KF, and 1 mg/ml BSA) containing 100 mM EDTA and 0.36 μg/ml PY20K (Eu-cryptate labeled anti-phosphotyrosine antibody, CIS Bio International) was added and after an additional 2 h incubation at rt, the plate was analyzed in a RUBYstar HTRF Reader.
24. m values was observed for all active compounds (Table 2).
25. M.A. McTigue, J.A. Wickersham, C. Pinko, R.E. Showalter, C.V. Parast, A. Tempczyk-Russell, M.R. Gehring, B. Mroczkowski, C.C. Kan, J.E. Villafranca, and K. Appelt Structure 7 1999 319
26. H.M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, and P.E. Bourne Protein Data Bank, Nucleic Acids Res. 28 2000 235
27. i values for the three selected compounds are listed in Table 3.
28. F. Eskens Br. J. Cancer 90 2004 1
29. 4 and absorbance was measured at 450 nm.