Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 23, 2009, Pages 6670-6674

  Luke, Richard W A ^a   Ballard, Peter ^a   Buttar, David ^a   Campbell, Leonie ^a   Curwen, Jon ^a   Emery, Steve C ^a   Griffen, Alison M ^a   Hassall, Lorraine ^a   Hayter, Barry R ^a   Jones, Cliff D ^a   McCoull, William ^a   Mellor, Martine ^a   Swain, Mike L ^a   Tucker, Julie A ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Angiogenesis; Inhibition; Kinase; Small molecule; TEK; Tie 2

Indexed keywords

ANGIOGENESIS INHIBITOR; ANGIOPOIETIN RECEPTOR; ANTINEOPLASTIC AGENT; MYOTONIC DYSTROPHY PROTEIN KINASE; PHOSPHOTRANSFERASE INHIBITOR; THIAZOLOPYRIMIDINE KINASE INHIBITOR; THIENOPYRIMIDINE KINASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CRYSTAL STRUCTURE; DRUG INHIBITION; DRUG POTENCY; IN VITRO STUDY; IN VIVO STUDY; STRUCTURE ACTIVITY RELATION;

CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PYRIMIDINES; RECEPTOR, TIE-2; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 72049097706     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.10.001     Document Type: Article

References (25)

1. Folkman J. Annu. Rev. Med. 57 (2006) 1
2. Morgensztern D., and Govindan R. Exp. Rev. Anticancer Ther. 6 (2006) 545
3. Kim I., Kim H.G., Moon S.-O., Chac S.W., So J.-N., Koh K.N., Ahn B.C., and Koh G.Y. Circ. Res. 86 (2000) 952
4. Thurston G. Cell Tissue Res. 314 (2003) 61
5. Kim K.L., Shin I.-S., Kim J.-M., Choi J.-H., Byun J., Jeon E.-S., Suh W., and Kim D.-K. Cardiovascular Res. 72 (2006) 394
6. 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
7. Ji Z., Ahmed A.A., Albert D.H., Bouska J.J., Bousquet P.F., Cunha G.A., Glaser K.B., Guo J., Li J., Marcotte P.A., Moskey M.D., Pease L.J., Stewart K.D., Yates M., Davidsen S.L., and Michaelides M.R. Bioorg. Med. Chem. Lett. 16 (2006) 4326
8. Hodous B.L., Geuns-Meyer S.D., Hughes P.E., Albrecht B.K., Bellon S., Bready J., Caenepeel S., Cee V.J., Chaffee S.C., Coxon A., Emery M., Fretland J., Gallant P., Gu Y., Hoffman D., Johnson R.E., Kendall R., Kim J.L., Long A.M., Morrison M., Olivieri P.R., Patel V.F., Polverino A., Rose P., Tempest P., Wang L., Whittington D.A., and Zhao H. J. Med. Chem. 50 (2007) 611
9. Cee V.J., Albrecht B.K., Geuns-Meyer S., Hughes P., Bellon S., Bready J., Caenepeel S., Chaffee S.C., Coxon A., Emery M., Fretland J., Gallant P., Gu Y., Hodous B.L., Hoffman D., Johnson R.E., Kendall R., Kim J.L., Long A.M., McGowan D., Morrison M., Olivieri P.R., Patel V.F., Polverino A., Powers D., Rose P., Wang L., and Zhao H. J. Med. Chem. 50 (2007) 627
10. Hodous B.L., Geuns-Meyer S.D., Hughes P.D., Albrecht B.K., Bellon S., Caenepeel S., Cee V.J., Chaffee S.C., Emery M., Fretland J., Gallant P., Gu Y., Johnson R.E., Kim J.L., Long A.M., Morrison M., Olivieri P.R., Patel V.F., Polverino A., Rose P., Wang L., and Zhao H. Bioorg. Med. Chem. Lett. 17 (2007) 2886
11. Buttar D., Edge M., Emery S.C., Fitzek M., Forder C., Griffen A., Hayter B., Hayward C.F., Hopcroft P.J., Luke R.W.A., Page K., Stawpert J., and Wright A. Bioorg. Med. Chem. Lett. 18 (2008) 4723
12. Luke, R. W. A.; Jones, C. D.; McCoull, W.; Hayter, B. R. WO Patent 2004013141, 2004.
13. 7 In the development of this assay we used an anti-Tie-2 antibody to show that, unlike phospho-Tie-2, total Tie-2 levels were not reduced by a diverse set of Tie-2 inhibitors.
14. 21 has been deposited in the Protein Data Bank (2wqb) together with structure factors and detailed experimental conditions.
15. DeLano, W. L. The PyMOL Molecular Graphics System; DeLano Scientific: San Carlos, CA, USA, 2002. http://www.pymol.org.
16. 13 as for VEGF. Briefly, anesthesia was induced in male Alderley Park rats using α-chloralose (iv) and then maintained with thiopentone (ip). The carotid artery was cannulated to enable blood pressure recording using a pressure transducer. The jugular vein was cannulated to allow VEGF or Ang-1 administration as a bolus injection in 0.85% sodium chloride. To give the most comparable data the dose of Ang-1 used was adjusted to induce a consistent blood pressure fall of between 10 and 20 mmHg to control for slight differences in the level of functional Ang-1 across batches (40-60 μg of Ang-1 depending on the batch). Compound 30 or vehicle alone [25% (w/v) hydroxypropyl-β-cyclodextrin in Sorensons phosphate buffer (pH 5.5)] was administered iv and blood pressure recorded. Consistent effects on blood pressure were seen in repeat experiments.
17. Wedge S.R., Ogilvie D.J., Dukes M., Kendrew J., Chester R., Jackson J.A., Boffey S.J., Valentine P.J., Curwen J.O., Musgrove H.L., Graham G.A., Hughes G.D., Thomas A.P., Stokes E.S.E., Curry B., Richmond G.H.P., Wadsworth P.F., Bigley A.L., and Hennequin L.F. Cancer Res. (2002) 4645
18. Curwen J.O., Musgrove H.L., Kendrew J., Richmond G.H.P., Ogilvie D., and Wedge S.R. Clin. Can. Res. 14 (2008) 3124
19. CCP4 Acta Crystallogr., Sect. D 1994, D50, 760-763.
20. quanta2000; Accelrys.
21. cnx Version 2000.1; Accelrys.
22. Refmac version 5.1.17:. Murshudov G.N., Vagin A.A., and Dodson E.J. Acta Crystallogr., Sect. D 53 (1997) 240
23. Bricogne, G.; Blanc, E.; Brandl, M.; Flensburg, C.; Keller, P.; Paciorek, W.; Roversi, P.; Smart, O.; Vonrhein, C.; Womack, T. Buster Version 1.3.1; Global Phasing Limited, 2008.
24. Coot, Emsley P., and Cowtan K. Acta Crystallogr., Sect. D 60 (2004) 2126
25. 2, respectively.