Discovery of a 5 H-benzo[4,5]cyclohepta[1,2-b ]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer

Journal of Medicinal Chemistry

Volumn 54, Issue 12, 2011, Pages 4092-4108

  Katz, Jason D ^a   Jewell, James P ^a   Guerin, David J ^a   Lim, Jongwon ^a   Dinsmore, Christopher J ^a   Deshmukh, Sujal V ^a   Pan, Bo Sheng ^a   Marshall, C Gary ^a   Lu, Wei ^a   Altman, Michael D ^a   Dahlberg, William K ^a   Davis, Lenora ^a   Falcone, Danielle ^a   Gabarda, Ana E ^a   Hang, Gaozhen ^a   Hatch, Harold ^a   Holmes, Rachael ^a   Kunii, Kaiko ^a   Lumb, Kevin J ^a   Lutterbach, Bart ^a   Mathvink, Robert ^a   Nazef, Naim ^a   Patel, Sangita B ^a   Qu, Xianlu ^a   Reilly, John F ^a   Rickert, Keith W ^a   Rosenstein, Craig ^a   Soisson, Stephen M ^a   Spencer, Kerrie B ^a   Szewczak, Alexander A ^a   Walker, Deborah ^a   Wang, Wenxian ^a   Young, Jonathan ^a   Zeng, Qinwen ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5H BENZO[4,5]CYCLOHEPTA[1,2 B]PYRIDIN 5 ONE; N (5 OXO 3 PHENYL 5H BENZO[4,5]CYCLOHEPTA[1,2 B]PYRIDIN 7 YL)METHANESULFONAMIDE; N [1,4 DIOXAN 2 YLMETHYL] N METHYL N' [3 (1 METHYL 1H PYRAZOL 4 YL) 5 OXO 5H BENZO[4,5]CYCLOHEPTA[1,2 B]PYRIDIN 7 YL]SULFURIC DIAMIDE; PHOSPHOTRANSFERASE INHIBITOR; SCATTER FACTOR RECEPTOR; SULFONAMIDE; UNCLASSIFIED DRUG; 5H BENZO(4,5)CYCLOHEPTA(1,2 B)PYRIDIN 5 ONE; 5H-BENZO(4,5)CYCLOHEPTA(1,2-B)PYRIDIN-5-ONE; ANTINEOPLASTIC AGENT; FUSED ALICYCLIC AROMATIC COMPOUND; PROTEIN TYROSINE KINASE; PYRAZOLE DERIVATIVE; PYRIDINE DERIVATIVE; RON PROTEIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOCHEMISTRY; CANCER INHIBITION; CRYSTAL STRUCTURE; DRUG STRUCTURE; FEMALE; MOUSE; NONHUMAN; PROTEIN PHOSPHORYLATION; STRUCTURE ACTIVITY RELATION; X RAY ANALYSIS; ANIMAL; CANCER TRANSPLANTATION; CHEMICAL STRUCTURE; DOG; DRUG ANTAGONISM; DRUG SCREENING; GENETICS; HAPLORHINI; HUMAN; MUTATION; NUDE MOUSE; PHOSPHORYLATION; PROTEIN BINDING; RAT; SYNTHESIS; TUMOR CELL LINE; X RAY CRYSTALLOGRAPHY; XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZOCYCLOHEPTENES; CELL LINE, TUMOR; CRYSTALLOGRAPHY, X-RAY; DOGS; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HAPLORHINI; HUMANS; MICE; MICE, NUDE; MODELS, MOLECULAR; MUTATION; NEOPLASM TRANSPLANTATION; PHOSPHORYLATION; PROTEIN BINDING; PYRAZOLES; PYRIDINES; RATS; RECEPTOR PROTEIN-TYROSINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; TRANSPLANTATION, HETEROLOGOUS;

EID: 79959405665     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200112k     Document Type: Article

References (55)

1. Longati, P.; Bardelli, A.; Ponzetto, C.; Naldini, L.; Comoglio, P. M. Tyrosines1234-1235 are Critical for Activation of the Tyrosine Kinase Encoded by the MET Proto-oncogene (HGF Receptor) Oncogene 1994, 9, 49-57
2. Birchmeier, C.; Birchmeier, W.; Gherardi, E.; Vande Woude, G. F. Met, Metastasis, Motility and More Nature Rev. Mol. Cell Biol. 2003, 4, 915-925 (Pubitemid 37493640)
3. Benvenuti, S.; Comoglio, P. M. The MET Receptor Tyrosine Kinase in Invasion and Metastasis J. Cell. Physiol. 2007, 213, 316-325 (Pubitemid 47509708)
4. Ponzetto, C.; Bardelli, A.; Zhen, Z.; Maina, F.; dalla Zonca, P.; Giordano, S.; Graziani, A.; Panayotou, G.; Comoglio, P. M. A Multifunctional Docking Site Mediates Signaling and Transformation by the Hepatocyte Growth Factor/Scatter Factor Receptor Family Cell 1994, 77, 261-271 (Pubitemid 24138623)
5. Brinkmann, V.; Foroutan, H.; Sachs, M; Weidner, K. M.; Birchmeier, W. Hepatocyte Growth Factor/Scatter Factor Induces a Variety of Tissue Specific Morphogenic Programs in Epithelial Cells J. Cell Biol. 1995, 131, 1573-1586
6. Bussolino, F.; Di Renzo, M. F.; Ziche, M.; Bocchietto, E.; Olivero, M.; Naldini, L.; Gaudina, G.; Tamagnone, L.; Coffer, A.; Comoglio, P. M. Hepatocyte Growth Factor is a Potent Angiogenic Factor Which Stimulates Endothelial Cell Motility and Growth J. Cell Biol. 1992, 119, 629-641
7. Gonzatti-Haces, M.; Seth, A.; Park, M.; Copeland, T.; Oroszlan, S.; Vande Woude, G. F. Characterization of the TPR-MET Oncogene p65 and the MET Protooncogene p140 Protein-Tyrosine Kinases Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 21-25
8. Schmidt, L.; Duh, F. M.; Chen, F.; Kishida, T.; Glenn, G.; Choyke, P.; Scherer, S. W.; Zhuang, Z.; Lubensky, I.; Dean, M.; Allikmets, R.; Chidambaram, A.; Bergerheim, U. R.; Feltis, J. T.; Casadevall, C.; Zamarron, A.; Bernues, M.; Richard, S.; Lips, C. J. M.; Walther, M. M.; Tsui, L.-C.; Geil, L.; Orcutt, M. L.; Stackhouse, T.; Lipan, J.; Slife, L.; Brauch, H.; Decker, J.; Niehans, G.; Hughson, M. D.; Moch, H.; Storkel, S.; Lerman, M. I.; Linehan, W. M.; Zbar, B. Germline and Somatic Mutations in the Tyrosine Kinase Domain of the MET Proto-oncogene in Papillary Renal Carcinomas Nature Genet. 1997, 16, 68-73 (Pubitemid 27198158)
9. Jeffers, M.; Fiscella, M.; Webb, C. P.; Anver, M.; Koochekpour, S.; Vande Woude, G. F. The Mutationally Activated Met Receptor Mediates Motility and Metastasis Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1441-14422
10. Christensen, J. G.; Burrows, J.; Salgia, R. c-Met as a Target for Human Cancer and Characterization of Inhibitors for Therapeutic Intervention Cancer Lett. 2005, 225, 1-26 (Pubitemid 40732764)
11. Smolen, G. A.; Sordella, R.; Muir, B.; Mohapatra, G.; Barmettler, A.; Archibald, H.; Kim, W. J.; Okimoto, R. A.; Bell, D. W.; Sgroi, D. C.; Christensen, J. G.; Settleman, J.; Haber, D. A. Amplification of MET May Identify a Subset of Cancers with Extreme Sensitivity to the Selective Tyrosine Kinase Inhibitor PHA-665752 Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 2316-2321 (Pubitemid 43271667)
12. Lutterbach, B.; Zeng, Q.; Davis, L. J.; Hatch, H.; Hang, G.; Kohl, N. E.; Gibbs, J. B.; Pan, B.-S. Lung Cancer Cell Lines Harboring MET Gene Amplification are Dependent on Met for Growth and Survival Cancer Res. 2007, 67, 2081-2088 (Pubitemid 46424226)
13. Engelman, J.A.; Zejnullahu, K.; Mitsudomi, T.; Song, Y.; Hyland, C.; Park, J. O.; Lindeman, N.; Gale, C. M.; Zhao, X.; Christensen, J.; Kosaka, T.; Holmes, A. J.; Rogers, A. M.; Cappuzzo, F.; Mok, T.; Lee, C.; Johnson, B. E.; Cantley, L. C.; Jänne, P. A. MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling Science 2007, 316, 1039-1043 (Pubitemid 46799492)
14. Bean, J.; Brennan, C.; Shih, J.-Y.; Riely, G.; Viale, A.; Wang, L.; Chitale, D.; Motoi, N.; Szoke, J.; Broderick, S.; Balak, M.; Chang, W.-C.; Yu, C.-J.; Gazdarl, A.; Pass, H.; Rusch, V.; Gerald, W.; Huang, S.-F.; Yang, P.-C.; Miller, V.; Ladanyi, M.; Yang, C.-H.; Pao, W. MET Amplification Occurs With or Without T790M Mutations in EGFR Mutant Lung Tumors with Acquired Resistance to Gefitinib or Erlotinib Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 20932-20937
15. Zou, H. Y.; Li, Q. H.; Lee, J. H.; Arango, M. E.; McDonnell, S. R.; Yamazaki, S.; Koudriakova, T. B.; Alton, G.; Cui, J. J.; Kung, P.-P.; Nambu, M. D.; Los, G.; Bender, S. L.; Mroczkowski, B.; Christensen, J. G. An Orally Available Small-molecule Inhibitor of c-Met, PF-2341066, Exhibits Cytoreductive Antitumor Efficacy Through Antiproliferative and Antiangiogenic Mechanisms Cancer Res. 2007, 67, 4408-4417 (Pubitemid 46815090)
16. Bellon, S. F.; Kaplan-Lefko, P. J.; Yang, Y.; Zhang, Y.; Moriguchi, J.; Rex, K.; Johnson, C. W.; Rose, P. E.; Long, A. M.; OConnor, A. B.; Gu, Y.; Coxon, A.; Kim, T.-S.; Tasker, A.; Burgess, T. L.; Dussault, I. c-Met inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-Related Mutations J. Biol. Chem. 2008, 283, 2675-2683
17. Zhang, Y. H.; Kaplan-Lefko, P. J.; Rex, K.; Yang, Y.; Moriguchi, J.; Osgood, T.; Mattson, B.; Coxon, A.; Reese, M.; Kim, T.-S.; Lin, J.; Chen, A.; Burgess, T. L.; Dussault, I. Identification of a Novel Recepteur dOrigine Nantais/c-Met Small-Molecule Kinase Inhibitor with Antitumor Activity in Vivo Cancer Res. 2008, 68, 6680-6687
18. Raeppel, S.; Claridge, S.; Saavedra, O.; Gaudette, F.; Zhan, L.; Mannion, M.; Zhou, N.; Raeppel, F.; Granger, M.-C.; Isakovic, L.; Déziel, R.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Robert, M.-F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang, J.; Ste-Croix, H.; Macleod, A. R.; Besterman, J.; Vaisburg, A. N -(3-Fluoro-4-(2-arylthieno[3,2- b ]pyridin-7-yloxy)phenyl)-2-oxo- 3-phenylimidazolidine-1-carboxamides: A Novel Series of Dual c-Met/VEGFR2 Receptor Tyrosine Kinase Inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 1323-1328
19. Schroeder, G. M.; An, Y.; Cai, Z.-W.; Chen, X.-T.; Clark, C.; Cornelius, L. A. M.; Dai, J.; Gullo-Brown, J.; Gupta, A.; Henley, B.; Hunt, J. T.; Jeyaseelan, R.; Kamath, A.; Kim, K.; Lippy, J.; Lombardo, L. J.; Manne, V.; Oppenheimer, S.; Sack, J. S.; Schmidt, R. J.; Shen, G.; Stefanski, K.; Tokarski, J. S.; Trainor, G. L.; Wautlet, B. S.; Wei, D.; Williams, D. K.; Zhang, Y.; Zhang, Y.; Fargnoli, J.; Borzilleri, R. M. Discovery of N -(4-(2-Amino-3- chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1, 2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily J. Med. Chem. 2009, 52, 1251-1254
20. Albrecht, B. K.; Harmange, J. C.; Bauer, D.; Berry, L.; Bode, C.; Boezio, A.; Chen, A.; Choquette, D.; Dussault, I.; Fridrich, C.; Hirai, S.; Hoffman, D.; Larrow, J. F.; Kaplan-Lefko, P.; Lin, J.; Lohman, J.; Long, A. M.; Moriguchi, J.; OConnor, A.; Potashman, M. H.; Reese, M.; Rex, K.; Siegmund, A.; Shah, K.; Shimanovich, R.; Springer, S. K.; Teffera, Y.; Yang, Y.; Zhang, Y.; Bellon, S. F. Discovery and Optimization of Triazolopyridazines as Potent and Selective Inhibitors of the c-Met Kinase J. Med. Chem. 2008, 51, 2879-2882 (Pubitemid 351706015)
21. DAngelo, 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
22. Boezio, A. A.; Berry, L.; Albrecht, B. K.; Bauer, D.; Bellon, S. F.; Bode, C.; Chen, A.; Choquette, D.; Dussault, I.; Hirai, S.; Kaplan-Lefko, P.; Larrow, J. F.; Lin, M.-H. J.; Lohman, J.; Potashman, M. H.; Rex, K.; Santostefano, M.; Shah, K.; Shimanovich, R.; Springer, S. K.; Teffera, Y.; Yang, Y.; Zhang, Y.; Harmange, J.-C. Discovery and Optimization of Potent and Selective Triazolopyridazine Series of c-Met Inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 6307-6312
23. Nishii, H.; Chiba, T.; Morikami, K.; Fukami, T. A.; Sakamoto, H.; Ko, K.; Koyano, H. Discovery of 6-benzyloxyquinolines as c-Met Selective Kinase Inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 1405-1409
24. Porter, J.; Lumb, S.; Lecomte, F.; Reuberson, J.; Foley, A.; Calmiano, M.; le Riche, K.; Edwards, H.; Delgado, J.; Franklin, R. J.; Gascon-Simorte, J. M.; Maloney, A.; Meier, C.; Batchelor, M. Discovery of a Novel series of Quinoxalines as Inhibitors of c-Met Kinase Bioorg. Med. Chem. Lett. 2009, 19, 397-400
25. Porter, J.; Lumb, S.; Franklin, R. J.; Gascon-Simorte, J. M.; Calmiano, M.; Riche, K. L.; Lallemand, B.; Keyaerts, J.; Edwards, H.; Maloney, A.; Delgado, J.; King, L.; Foley, A.; Lecomte, F.; Reuberson, J.; Meier, C.; Batchelor, M. Discovery of 4-azaindoles as Novel Inhibitors of c-Met Kinase Bioorg. Med. Chem. Lett. 2009, 19, 2780-2784
26. 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
27. Burgess, T.; Coxon, A.; Meyer, S.; Sun, J.; Rex, K.; Tsuruda, T.; Chen, Q.; Ho, S.-Y.; Li, L.; Kaufman, S.; McDorman, K.; Cattley, R. C.; Sun, J.; Elliott, G.; Zhang, K.; Feng, X.; Jia, X.-C.; Green, L.; Radinsky, R.; Kendall, R. Fully Human Monoclonal Antibodies to Hepatocyte Growth Factor with Therapeutic Potential Against Hepatocyte Growth Factor/c-Met-Dependent Human Tumors Cancer Res. 2006, 66, 1721-1729 (Pubitemid 43259957)
28. Martens, T.; Schmidt, N. O.; Eckerich, C.; Fillbrandt, R.; Merchant, M.; Schwall, R.; Westphal, M.; Lamszus, K. A Novel One-Armed Anti-c-Met Antibody Inhibits Glioblastoma Growth In Vivo Clin. Cancer Res. 2006, 12, 6144-6152 (Pubitemid 44703780)
29. Liu, X.; Yao, W.; Newton, R. C.; Scherle, P. A. Targeting the c-MET Signaling Pathway for Cancer Therapy Expert Opin. Invest. Drugs 2008, 17, 997-1011
30. Migliore, C.; Giordano, S. Molecular Cancer Therapy: Can Our Expectation be MET? Eur. J. Cancer 2008, 44, 641-651
31. Pan, B.-S.; Chan, G. K. Y.; Chenard, M.; Chi, A.; Davis, L. J.; Deshmukh, S. V.; Gibbs, J. B.; Gil, S.; Hang, G.; Hatch, H.; Jewell, J. P.; Kariv, I.; Katz, J. D.; Kunii, K.; Lu, W.; Lutterbach, B. A.; Paweletz, C. P.; Qu, X.; Reilly, J. F.; Szewczak, A. A.; Zeng, Q.; Kohl, N. E.; Dinsmore, C. J. MK-2461, a Novel Multitargeted Kinase Inhibitor, Preferentially Inhibits the Activated c-Met Receptor Cancer Res. 2010, 70, 1524-1533
32. Wang, J.; Della Penna, K.; Wang, H.; Karczewski, J.; Connolly, T. M.; Koblan, K. S.; Bennett, P. B.; Salata, J. J. Functional and Pharmacological Properties of Canine ERG Potassium Channels Am. J. Physiol.: Heart Circ. Physiol. 2003, 284, H256-H267
33. Dosed iv at 1 mg/kg as a solution in DMSO and po at 2 mg/kg as a solution in methylcellulose.
34. To streamline the discussion, certain compounds prepared by specific standard one-off chemical transformations have not been fully described in these schemes. However the synthesis of each compound in this manuscript is completely described in the Experimental Section and the Supporting Information.
35. Marcoux, J.-F.; Marcotte, F.-A.; Wu, J.; Dormer, P. G.; Davies, I. W.; Hughes, D.; Reider, P. J. A General Preparation of Pyridines and Pyridones via the Annulation of Ketones and Esters J. Org. Chem. 2001, 66, 4194-4199 (Pubitemid 32867556)
36. Brenner, D. G.; Halczenko, W.; Shepard, K. L. Imino-Bridged heterocycles II: Regiospecific Synthesis of the 11 H -benzo[5,6]cyclohepta[1,2- c ]pyridin-6,11-imine and 5 H -benzo[4,5]cyclohepta[1,2- b ]pyridin-5,10-imine Systems J. Heterocycl. Chem. 1982, 19, 897-900
37. Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. An Ammonia Equivalent for the Palladium-Catalyzed Amination of Aryl Halides and Triflates Tetrahedron Lett. 1997, 38, 6367-6370 (Pubitemid 27368167)
38. Alcaraz, L.; Bennion, C.; Morris, J.; Meghani, P.; Thom, S. M. Novel N -Aryl and N -Heteroaryl Sulfamide Synthesis via Palladium Cross Coupling Org. Lett. 2004, 6, 2705-2708 (Pubitemid 39118976)
39. Winum, J.-Y.; Toupet, L.; Barragon, V.; Dewynter, G.; Montero, J.-L. N -(tert -Butoxycarbonyl)- N -[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1- ylsulfonyl]azanide: A New Sulfamoylating Agent. Structure and Reactivity toward Amines Org. Lett. 2001, 3, 2241-2243 (Pubitemid 33627138)
40. Yang, B. H.; Buchwald, S. L. Palladium-Catalyzed Amination of Aryl Halides and Sulfonates J. Organomet. Chem. 1999, 576, 125-146 (Pubitemid 129595972)
41. Hartwig, J. F. Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism Angew. Chem., Int. Ed. 1998, 37, 2046-2067 (Pubitemid 28397936)
42. Wolfe, J.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Rational Development of Practical Catalysts for Aromatic Carbon-Nitrogen Bond Formation Acc. Chem. Res. 1998, 31, 805-818 (Pubitemid 128473631)
43. Netherton, M. R.; Fu, G. C. Air-Stable Trialkylphosphonium Salts: Simple, Practical, and Versatile Replacements for Air-Sensitive Trialkylphosphines. Applications in Stoichiometric and Catalytic Processes Org. Lett. 2001, 3, 4295-4298 (Pubitemid 33627269)
44. 50 refers to the ability to inhibit the phosphorylation of a synthetic peptide by the cytosolic portion of recombinant human c-Met, as measured in an HTRF assay. See Experimental Section details and ref 31 for a complete description.
45. Giordano, S.; Ponzetto, C.; Di Renzo, M. F.; Cooper, C. S.; Comoglio, P. M. Tyrosine Kinase Receptor Indistinguishable from the c-Met Protein Nature 1989, 339, 155-156 (Pubitemid 19122275)
46. Measured at Essen Biosciences in Chinese hamster lung cells (http://essenbioscience.com/servicesCardiacSafety.html).
47. a = 4.23 ± 0.20.
48. Identified by incubating the compound with rat and human hepatocytes and analysis of metabolites via HPLC and mass spectrometry.
49. Monomethyl 71 has been identified as a major metabolite of 59 in rat hepatocytes.
50. Rickert, K. W.; Patel, S. B.; Allison, T. J.; Byrne, N. J.; Darke, P. L.; Ford, R. D.; Guerin, D. J.; Hall, D. L.; Kornienko, M.; Lu, J; Munshi, S. K.; Reid, J. C.; Shipman, J. M.; Stanton, E. F.; Wilson, K. J.; Young, J. R.; Soisson, S. M.; Lumb, K. J. Structural Basis for Selective Small-Molecule Inhibition of the Phosphorylated c-Met Kinase Domain J. Biol. Chem. 2011, 286, 11218-11225
51. As predicted by density-functional theory (DFT) geometry calculations at the B3LYP/6-31 g* level.
52. 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 (Pubitemid 39005814)
53. Qi, J.; McTigue, M. A.; Rogers, A.; Lifshits, E.; Christensen, J. G.; Jänne, P. A.; Engelman, J. A. Multiple Mutations and Bypass Mechanisms Can Contribute to Development of Acquired Resistance to MET Inhibitors Cancer Res. 2011, 71, 1081-1091
54. Dussault, I.; Bellon, S. F. c-Met Inhibitors with Different Binding Modes Cell Cycle 2008, 7, 1157-1160
55. For an enantioselective synthesis of 81: Stewart, G. W.; Brands, K. M. J.; Brewer, S. E.; Cowden, C. J.; Davies, A. J.; Edwards, J. S.; Gibson, A. W.; Hamilton, S. E.; Katz, J. D.; Keen, S. P.; Mullens, P. R.; Scott, J. P.; Wallace, D. J.; Wise, C. S. Process Development and Large-Scale Synthesis of a c-Met Kinase Inhibitor Org. Process Res. Dev. 2010, 14, 849-858