Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 6, 2007, Pages 1773-1778

  Miyazaki, Yasushi ^a   Tang, Jun ^b   Maeda, Yutaka ^a   Nakano, Masato ^a   Wang, Liping ^b   Nolte, Robert T ^b   Sato, Hideyuki ^a   Sugai, Masaki ^a   Okamoto, Yuji ^a   Truesdale, Anne T ^b   Hassler, Daniel F ^b   Nartey, Eldridge N ^b   Patrick, Denis R ^b   Ho, Maureen L ^b   Ozawa, Kazunori ^a  

^a Development and Medical Affairs Division   (Japan)

^b GLAXOSMITHKLINE   (United States)

Author keywords

Angiogenesis; Kinase inhibitor; Receptor tyrosine kinase; Tie 2; VEGFR2

Indexed keywords

4 AMINO 5 [4 [[2 FLUORO 5 (TRIFLUOROMETHYL)PHENYL]AMINOCARBONYLAMINO]PHENYL]FURO[2,3 D]PYRIMIDINE; ANGIOGENESIS INHIBITOR; ANGIOPOIETIN RECEPTOR; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 2;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIANGIOGENIC ACTIVITY; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DOSE TIME EFFECT RELATION; ENZYME INHIBITION; GROWTH INHIBITION; MOUSE; NONHUMAN; XENOGRAFT;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTINEOPLASTIC AGENTS; AREA UNDER CURVE; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; DRUG EVALUATION, PRECLINICAL; FEMALE; HT29 CELLS; HUMANS; INDICATORS AND REAGENTS; MALE; MICE; MODELS, MOLECULAR; NEOPLASM TRANSPLANTATION; PYRIMIDINES; RECEPTOR, TIE-2; RNA; UREA; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 33847159338     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.12.077     Document Type: Article

References (18)

1. Folkman J. N. Engl. J. Med. 285 (1971) 1182
2. Yancopoulos G.D., Davis S., Gale N.W., Rudge J.S., Wiegand S.J., and Holash J. Nature 407 (2000) 242
3. Veikkola T., Karkkainen M., Claesson-Welsh L., and Alitalo K. Cancer Res. 60 (2000) 203
4. Jones N., Iljin K., Dumont D.J., and Alitalo K. Nat. Rev. Mol. Cell Biol. 2 (2001) 257
5. Millauer B., Longhi M.P., Plate K.H., Shawver L.K., Risau W., Ullrich A., and Strawn L.M. Cancer Res. 56 (1996) 1615
6. Wedge S.R., Ogilvie D.J., Dukes M., Kendrew J., Curwen J.O., Hennequin L.F., Thomas A.P., Stokes E.S., Curry B., Richmond G.H., and Wadsworth P.F. Cancer Res. 60 (2000) 970
7. Shim W.S., Teh M., Mack P.O., and Ge R. Int. J. Cancer 94 (2001) 6
8. Siemeister G., Schirner M., Weindel K., Reusch P., Menrad A., Marme D., and Martiny-Baron G. Cancer Res. 59 (1999) 3185
9. Miyazaki Y., Matsunaga S., Tang J., Maeda Y., Nakano M., Philippe R.J., Shibahara M., Liu W., Sato H., Wang L., and Nolte R.T. Bioorg. Med. Chem. Lett. 15 (2005) 2203
10. Cheung, M.; Harris, P. A.; Hasegawa, M.; Ida S.; Kano K.; Nishigaki N.; Sato, H.; Veal, J. M.; Washio, Y.; West, R. I. PCT Application, WO2002044156.
11. -.
12. 2, 0.3 mM DTT, 0.1 mg/ml BSA and test compound in 100 mM HEPES, pH 7.5.
13. Dai Y., Guo Y., Frey R.R., Ji Z., Curtin M.L., Ahmed A.A., Albert D.H., Arnold L., Arries S.S., Barlozzari T., Bauch J.L., Bouska J.J., Bousquet P.F., Cunha G.A., Glaser K.B., Guo J., Li J., Marcotte P.A., Marsh K.C., Moskey M.D., Pease L.J., Stewart K.D., Stoll V.S., Tapang P., Wishart N., Davidsen S.K., and Michaelides M.R. J. Med. Chem. 48 (2005) 6066
14. 2 incubator. Compounds were dissolved in 100% DMSO and serially diluted twofold for 20 points. Compounds were diluted into DMEM, then diluted into the cell plates at a final dilution of 1:500 yielding a final DMSO concentration of 0.2%. Plates were incubated for three days and then developed with Promega CellTiter-Glo reagent and read on a Perkin-Elmer Victor V plate reader. Curves are fit to a four parameter model using XLfit and the inflection point is recorded as the EC50.
15. max and AUC (limited) by 1.9- and 2.6-fold, respectively.
16. Rieder M.J., O'Drobinak D.M., and Greene A.S. Microvasc. Res. 49 (1995) 180
17. Adams J., Huang P., and Patrick D. Curr. Opin. Chem. Biol. 6 (2002) 486
18. 50 are >10 μM against CDK2, EGFR, GSK3 and <100 nM against SRC and VEGFR3) as far as the inhibitory activity was measured. However, it was found that some substituents on 6-position could change selectivity profile on certain targets (data are not shown)