Design and effective synthesis of novel templates, 3,7-diphenyl-4-amino-thieno and furo-[3,2-c]pyridines as protein kinase inhibitors and in vitro evaluation targeting angiogenetic kinases

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 1, 2007, Pages 250-254

  Miyazaki, Yasushi ^a   Nakano, Masato ^a   Sato, Hideyuki ^a   Truesdale, Anne T ^b   Stuart, J Darren ^b   Nartey, Eldridge N ^b   Hightower, Kendra E ^b   Kane Carson, Laurie ^b  

^a Development and Medical Affairs Division   (Japan)

^b GLAXOSMITHKLINE   (United States)

Author keywords

Angiogenesis; EphB4; Protein kinase; Tie 2; VEGFR2

Indexed keywords

3,7 DIPHENYL 4 AMINOFURO[3,2 C]PYRIDINE; 3,7 DIPHENYL 4 AMINOTHIENO[3,2 C]PYRIDINE; PROTEIN KINASE INHIBITOR;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; NONHUMAN; PHARMACOPHORE; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

3T3 CELLS; ADENOSINE TRIPHOSPHATE; ANGIOGENESIS INHIBITORS; ANIMALS; BINDING, COMPETITIVE; DRUG DESIGN; FURANS; MICE; PROTEIN KINASE INHIBITORS; PYRIDINES; RECEPTOR, EPHB4; RECEPTOR, TIE-2; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 33845668264     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.09.050     Document Type: Article

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19. 2, 1 mM DTT, 5 mM KCl, 1 mM CHAPS, 0.1 mg/mL BSA, and test compound in 100 mM HEPES.
20. EphB4 autophosphorylation at the cellular level was determined by ELISA using recombinant NIH3T3 cells (cFms-EphB4) with the stable expression of the chimeric receptors of cFms-derived extracellular domain and EphB4-derived intracellular domain. The test compound was incubated with cFms-EphB4 for 1 h after serum starvation. The cells were stimulated with a specific ligand, M-CSF (macrophage colony stimulating factor), to induce the activation of the cFms-EphB4 receptors. The phosphorylation level of the receptors was measured by the incubation of the ELISA plate capturing the protein via anti-cFms antibody with anti-phosphotyrosine antibody and visualized by incubating with chemiluminescent substrates.
21. 50 of 9f against VEGFR2 and Tie-2 is 1.9 μM and over 20 μM, respectively.
22. Compound 15c showed comparable potency against VEGFR2 and Tie-2 against 4-amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine, which was published in our previous report (see Ref. 6). It should be noted that assay condition was slightly modified from the previous one.
23. Bromination of compound 13 occurred at 2-position as well as 7-position, resulting in low yield.