Pyridinylimidazole inhibitors of Tie2 kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 17, 2007, Pages 4756-4760

  Semones, Marcus ^a   Feng, Yanhong ^a   Johnson, Neil ^a   Adams, Jerry L ^a   Winkler, Jim ^c   Hansbury, Michael ^b  

^a GLAXOSMITHKLINE   (United States)

^b Incyte Pharm ^*  (United States)

^c ARRAY BIOPHARMA INC   (United States)

Author keywords

Imidazole; Tie2 kinase; Xenograft

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; IMIDAZOLE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR;

ANGIOGENESIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER GRAFT; CANCER INHIBITION; CONTROLLED STUDY; DRUG EFFICACY; IN VIVO STUDY; MOUSE; NONHUMAN; PLASMACYTOMA; TUMOR GROWTH;

ANIMALS; CELL LINE, TUMOR; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; IMIDAZOLES; INHIBITORY CONCENTRATION 50; MICE; MODELS, CHEMICAL; MODELS, MOLECULAR; NEOPLASM TRANSPLANTATION; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PLASMACYTOMA; PYRIDINES; RECEPTOR, TIE-2;

EID: 34547543902     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.06.068     Document Type: Article

References (15)

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12. An ortep view of compound 10. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 644904. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk]. {A figure is presented}
13. Compound 1 was tested in our Tie2 receptor signal transduction assay and our Tie2 autophosphorylation assay. Compounds 5 and 10 were tested in our Tie2 autophosphorylation assay. For assay conditions see Semones, M. A. PCT Int. Appl. (2002), WO 2002060382 and Adams, J. L.; Kasparec, J.; Silva, D.; Yuan, C. C. K. PCT Int. Appl. (2003), WO 2003029209.
14. Compound 5 has a >10-fold selectivity against VEGFR2, VEGFR3, and PDGFR1β.
15. The homology model of Tie2 was generated in the program MOE using the crystal structure FGFR-2 kinase (PDB code 1oec) as the structural template; compounds 1 and 5 were manually docked into the homology model based on the bound conformation of SB-203850 in crystal structure 1a9u. Figure 2 depicts the manual docking model for compound 5 in a second-generation homology model of an active form of Tie2; this second-generation homology model was generated in the program MOE using the crystal structures of inactive Tie2 (PDB code 1fvr) and active FGFR-2 kinase (PDB code 1oec) as structural templates. Figures were generated using the program pymol.