Journal of Medicinal Chemistry
Article
(7) (a) Fujiwara, Y.; Senga, Y.; Nishitoba, T.; Osawa, T.; Miwa, A.;
Nakamura, K. Preparation of quinoline derivatives and quinazoline
derivatives inhibiting autophosphorylation of hepatocyte growth factor
receptor as antitumor agents. PTC Int. Appl. WO 2003000660A1,
2003, 441 pp. (b) Enzyme activities were generated internally.
(8) As we have postulated previously, it might be useful to employ
two types of c-Met inhibitors to treat c-Met-dependent tumors: very
potent and selective class I inhibitors of wild-type c-Met and class II
inhibitors that inhibit a wider range of c-Met mutations than those
inhibited by class I molecules, thereby offering more treatment options
for cancer patients. Dussault, I.; Bellon, S. F. c-Met inhibitors with
different binding modes. Cell Cycle 2008, 7 (9), 1157−1160.
(9) (a) Berthou, S.; Aebersold, D. M.; Schmidt, L. S.; Stroka, D.;
Heigl, C.; Streit, B.; Stalder, D.; Gruber, G.; Liang, C.; Howlett, A. R.;
Candinas, D.; Greiner, R. H.; Lipson, K. E.; Zimmer, Y. The Met
kinase inhibitor SU11274 exhibits a selective inhibition pattern toward
different receptor mutated variants. Oncogene 2004, 23, 5387−5393.
(b) Buchanan, S. G.; Hendle, J.; Lee, P. S.; Smith, C. R.; Bounaud, P.-
Y.; Jessen, K. A.; Tang, C. M.; Huser, N. H.; Felce, J. D.; Froning, K. J.;
Peterman, M. C.; Aubol, B. E.; Gessert, S. F.; Sauder, J. M.; Schwinn,
K. D.; Russell, M.; Rooney, I. A.; Adams, J.; Leon, B. C.; Do, T. H.;
Blaney, J. M.; Sprengeler, P. A.; Thompson, D. A.; Smyth, L.; Pelletier,
L. A.; Atwell, S.; Holme, K.; Wasserman, S. R.; Emtage, S.; Burley, S.
K.; Reich, S. H. SGX523 is an exquisitely selective, ATP-competitive
inhibitor of the MET receptor tyrosine kinase with antitumor activity
in vivo. Mol. Cancer Ther. 2009, 8, 3181−3190.
(10) D’Angelo, N. D.; Bellon, S. F.; Booker, S. K.; Cheng, Y.; Coxon,
A.; Dominguez, C.; Fellows, I.; Hoffman, D.; Hungate, R.; Kaplan-
Lefko, P.; Lee, M. R.; Li, C.; Liu, L.; Rainbeau, E.; Reider, P. J.; Rex,
K.; Siegmund, A.; Sun, Y.; Tasker, A. S.; Xi, N.; Xu, S.; Yang, Y.;
Zhang, Y.; Burgess, T. L.; Dussault, I.; Kim, T.-S. Design, synthesis,
and biological evaluation of potent c-Met inhibitors. J. Med. Chem.
2008, 51, 5766−5779.
(11) Besides pyrazolones, 6-membered heterocycles also show good
c-Met activities: (a) Choquette, D.; Bellon, S.; Dussault, I., Harmange,
J.-C.; Kim, T.-S.; Rex, K.; Roveto P. Pyridones: A New Class of Orally
Bioavailable and Selective c-Met Inhibitors. Gordon Research
Conference, Colby-Sawyer College, New London, NH, August 5−
10, 2007. (b) Kim, K. S.; Zhang, L.; Schmidt, R.; Cai, Z.-W.; Wei, D.;
Williams, D. K.; Lombardo, L. J.; Trainor, G. L.; Xie, D.; Zhang, Y.;
An, Y.; Sack, J. S.; Tokarski, J. S.; Darienzo, C.; Kamath, A.; Marathe,
P.; Zhang, Y.; Lippy, J.; Jeyaseelan, R. Sr.; Wautlet, B.; Henley, B.;
Gullo-Brown, J.; Manne, V.; Hunt, J. T.; Fargnoli, J.; Borzilleri, R. M.
Discovery of pyrrolopyridine−pyridone based inhibitors of Met
kinase: synthesis, X-ray crystallographic analysis, and biological
activities. J. Med. Chem. 2008, 51, 5330−5341.
pharmacokinetic support, Douglas Whittington for his
assistance with the X-ray crystallographic data, Yajing Yang
and Yihong Zhang for conducting the enzyme and cell-based
assays, and Alex Long for protein purification.
ABBREVIATIONS USED
■
RTK, receptor tyrosine kinase; EGFR, epidermal growth factor
receptor; VEGFR-2, vascular endothelial growth factor receptor
2; IGF-1R, insulin-like growth factor receptor 1; ATP,
adenosine-5′-triphosphate; DCM, dichloromethane; BSA,
bovine serum albumin; HGF, hepatocyte growth factor;
HLM, human liver microsomes; RLM, rat liver microsomes;
iv, intravenous; SAR, structure−activity relationship; PK,
pharmacokinetic; PD, pharmacodynamic; TFA, trifluoroacetic
acid; LDA, lithium diisopropylamide; HATU, 2-(7-aza-1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate; rt, room temperature
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(16) See Supporting Information for assay protocols.
(17) During the preparation of this manuscript, imidazolidine-based
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