Arylphthalazines. Part 2: 1-(Isoquinolin-5-yl)-4-arylamino phthalazines as potent inhibitors of VEGF receptors I and II

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 6, 2006, Pages 1579-1581

  Duncton, Matthew A J ^a   Piatnitski, Evgueni L ^a   Katoch Rouse, Reeti ^a   Smith II, Leon M ^a   Kiselyov, Alexander S ^a,b   Milligan, Daniel L ^a   Balagtas, Chris ^a   Wong, Wai C ^a   Kawakami, Joel ^a   Doody, Jacqueline F ^a  

^a ELI LILLY AND COMPANY   (United States)

^b CHEMDIV INC   (United States)

Author keywords

Angiogenesis; Kinase inhibitor; Phthalazine; Vascular endothelial growth factor

Indexed keywords

ISOQUINOLIN 5 YL; PHTHALAZINE DERIVATIVE; PYRAZOL 4 YL; QUINOLINE 5 YL; UNCLASSIFIED DRUG; VANDETANIB; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; ZD 2171;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYMATIC ASSAY; FLUORESCENCE ANALYSIS; IC 50;

FLUOROIMMUNOASSAY; HUMANS; INHIBITORY CONCENTRATION 50; ISOQUINOLINES; PHTHALAZINES; STRUCTURE-ACTIVITY RELATIONSHIP; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 32044445020     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.12.045     Document Type: Article

References (11)

1. M. Klagsbrun, and M.A. Moses Chem. Biol. 6 1999 R217
2. ® (Bevacizumab) has recently been approved to treat colorectal cancer; see C. Culy Drugs Today 41 2005 23
3. ® (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
4. 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
5. J. Dumas, and J.A. Dixon Exp. Opin. Ther. Pat. 15 2005 647
6. 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
7. E.L. Piatnitski, M.A.J. Duncton, A. Kiselyov, R. Katoch-Rouse, D. Sherman, D. Milligan, C. Balagtas, W.C. Wong, J. Kawakami, and J.F. Doody Bioorg. Med. Chem. Lett. 15 2005 4696
8. S. Guery, I. Parrot, Y. Rival, and C.G. Wermuth Synthesis 2001 699
9. 2, 2 mM DTT, and 1 mg/ml BSA) containing 0.5 mmol pGAT-biotin and 3-4 ng KDR enzyme is added to each well. After 5-10 min preincubation, the kinase reaction is initiated by the addition of 10 μl of 10 μM ATP in reaction buffer, after which the plate is incubated at room temperature for 45 min. The reaction is stopped by addition of 50 μl KF buffer (50 mM Hepes, pH 7.5, 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). After 30 min, 100 μl of 10 nM SV-XL (modified APC-labeled streptavidin, CIS Bio International) in KF buffer is added, and after an additional 2 h incubation at room temperature, the plate is read in a RUBYstar HTRF Reader.
10. 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
11. For example, the percentage inhibition for compound (6) against these kinases at a screening concentration of 10 μM is as follows: c-Met, 2%; EGFR, 13%; FLT-3, 33%; IGF-1R, 25%; InsR, 10% (average of n = 3 or n = 2). A percentage inhibition of <40% at 10 μM is considered to be inactive in our hands.