Imidazo[1,5-a]pyrazines: Orally efficacious inhibitors of mTORC1 and mTORC2

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 7, 2011, Pages 2092-2097

  Crew, Andrew P ^a   Bhagwat, Shripad V ^a   Dong, Hanqing ^a   Bittner, Mark A ^a   Chan, Anna ^a   Chen, Xin ^a   Coate, Heather ^a   Cooke, Andrew ^a   Gokhale, Prafulla C ^a   Honda, Ayako ^a   Jin, Meizhong ^a   Kahler, Jennifer ^a   Mantis, Christine ^a   Mulvihill, Mark J ^a   Tavares Greco, Paula A ^a   Volk, Brian ^a   Wang, Jing ^a   Werner, Douglas S ^a   Arnold, Lee D ^a   Pachter, Jonathan A ^a   Wild, Robert ^a   Gibson, Neil W ^a   more..

^a OSI PHARMACEUTICALS INC   (United States)

Author keywords

Imidazo 1,5 a pyrazine; mTOR; mTORC1; mTORC2; Oral inhibitor

Indexed keywords

1 (3 CHLOROPYRAZIN 2 YL)METHYLAMINE; 3 METHYLIDENECYCLOBUTANE CARBOXYLIC ACID; IMIDAZO [1,5 A]PYRAZIN 8 AMINE; IMIDAZO [1,5 A]PYRAZINE DERIVATIVE; IMIDAZOPYRAZINE 3 CYCLOBUTYL DERIVATIVE; IMIDAZOPYRAZINE 3 CYCLOHEXYL DERIVATIVE; IMIDAZOPYRAZINE 3 PIPERIDIN 4 YL DERIVATIVE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; OSI 027; PYRAZINE DERIVATIVE; SOMATOMEDIN C RECEPTOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; BINDING SITE; CANCER INHIBITION; CONTROLLED STUDY; DISTRIBUTION VOLUME; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STABILITY; DRUG STRUCTURE; ENZYME LINKED IMMUNOSORBENT ASSAY; HIGH THROUGHPUT SCREENING; HYDROGEN BOND; IN VIVO STUDY; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

ADMINISTRATION, ORAL; CELL LINE, TUMOR; HUMANS; IMIDAZOLES; MODELS, MOLECULAR; PROTEINS; PYRAZINES; TRANSCRIPTION FACTORS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 79952487495     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.139     Document Type: Article

References (29)

1. (a) Faivre, S.; Kroemer, G.; Raymond, E. Nat. Rev. Drug Disc. 2006, 5, 671;
2. (b) Guertin, D. A.; Sabatini, D. M. Cancer Cell 2007, 12, 9;
3. (c) Wullschleger, S.; Loewith, R.; Hall, M. N. Cell 2006, 124, 471;
4. (d) Chiang, G. G.; Abraham, R. T. Trends Mol. Med. 2007, 13, 433;
5. (e) Meric-Bernstam, F.; Gonzalez-Angulo, A. M. J. Clin. Oncol. 2009, 27, 2278.
6. (a) Laplante, M.; Sabatini, D. M. J. Cell Sci. 2009, 122, 3589;
7. (b) Proud, C. G. Biochem. Soc. Trans. 2009, 37, 227.
8. (a) Loewith, R.; Jacinto, E.; Wullschleger, S.; Lorberg, A.; Crespo, J. L.; Bonenfant, D.; Oppliger, W.; Jenoe, P.; Hall, M. N. Mol. Cell 2002, 10, 457;
9. (b) Hay, N.; Sonenberg, N. Genes Dev. 2004, 18, 1926.
10. (a) Sarbassov, D. D.; Guertin, D. A.; Ali, S. M.; Sabatini, D. M. Science 2005, 307, 1098;
11. (b) Engelman, J. A. Nat. Rev. Cancer 2009, 9, 550.
12. O'Reilly, K. E.; Rojo, F.; She, Q.-B.; Solit, D.; Mills, G. B.; Smith, D.; Lane, H.; Hofmann, F.; Hicklin, D. J.; Ludwig, D. L.; Baselga, J.; Rosen, N. Cancer Res. 2006, 66, 1500.
13. (a) Bhagwat, S. V.; Crew, A. P.; Gokhale, P. C.; Yao, Y.; Kahler, J.; Arnold, L. D.; Epstein, D. M.; Wild, R.; Pachter, J. A. Abstr. Am. Assoc. Cancer Res. 2009, 100, 3711;
14. (b) Bhagwat, S. V.; Crew, A. P.; Gokhale, P. C.; Yao, Y.; Kahler, J.; Epstein, D. M.; Wild, R.; Pachter, J. A. Abstr. Am. Assoc. Cancer Res. 2010, 101, 4487;
15. (c) Choo, A. Y.; Yoon, S.-O.; Kim, S. G.; Roux, P. P.; Blenis, J. PNAS 2008, 105, 17414.
16. (a) Raynaud, F. I.; Eccles, S.; Clarke, P. A.; Hayes, A.; Nutley, B.; Alix, S.; Henley, A.; Di-Stefano, F.; Ahmad, Z.; Guillard, S.; Bjerke, L. M.; Kelland, L.; Valenti, M.; Patterson, L.; Gowan, S.; Brandon, A. H.; Hayakawa, M.; Kaizawa, H.; Koizumi, T.; Ohishi, T.; Patel, S.; Saghir, N.; Parker, P.; Waterfield, M.; Workman, P. Cancer Res. 2007, 67, 5840;
17. (b) Maira, S.-M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chène, P.; Pover, A. D.; Schoemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; García-Echeverría, C. Mol. Cancer Ther. 2008, 7, 1851;
18. (c) Chresta, C. M.; Davies, B. R.; Hickson, I.; Harding, T.; Cosulich, S.; Critchlow, S. E.; Vincent, J. P.; Ellston, R.; Jones, D.; Sini, P.; James, D.; Howard, Z.; Dudley, P.; Hughes, G.; Smith, L.; Maguire, S.; Hummersone, M.; Malagu, K.; Menear, K.; Jenkins, R.; Jacobsen, M.; Smith, G. C. M.; Guichard, S.; Pass, M. Cancer Res. 2010, 70, 288;
19. (d) Thoreen, C. C.; Kang, S. A.; Chang, J. W.; Liu, Q.; Zhang, J.; Gao, Y.; Reichling, L. J.; Sim, T.; Sabatini, D. M.; Gray, N. S. J. Biol. Chem. 2009, 284, 8023;
20. (e) Apsel, B.; Blair, J. A.; Gonzalez, B.; Nazif, T. M.; Feldman, M. E.; Aizenstein, B.; Hoffman, R.; Williams, R. L.; Shokat, K. M.; Knight, Z. A. Nat. Chem. Biol. 2008, 4, 691;
21. (f) Yu, K.; Shi, C.; Toral-Barza, L.; Lucas, J.; Shor, B.; Kim, J. E.; Zhang, W.-G.; Mahoney, R.; Gaydos, C.; Tardio, L.; Kim, S. K.; Conant, R.; Curran, K.; Kaplan, J.; Verheijen, J.; Ayral-Kaloustian, S.; Mansour, T. S.; Abraham, R. T.; Zask, A.; Gibbons, J. J. Cancer Res. 2010, 70, 621;
22. (g) Jessen, K.; Wang, S.; Kessler, L.; Guo, X.; Kucharski, J.; Staunton, J.; Lan, L.; Elia, M.; Stewart, J.; Bown, J.; Li, L. Mol. Cancer Ther. 2009, 8, B148.
23. Bhagwat, S. V.; Crew, A. P. Curr. Opin. Invest. Drugs 2010, 11, 638.
24. Bhagwat, S. V.; Kahler, J.; Yao, Y.; Maresca, P.; Brooks, M.; Crew, A.; Boisclair, M.; Pachter, J. A. Assay Drug Dev. Technol. 2009, 7, 471.
25. Mulvihill, M. J.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.; Foreman, K.; Landfair, D.; O'Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.; Arnold, L. D.; Gibson, N. W.; Ji, Q. S. Future Med. Chem. 2009, 1, 1153.
26. Mulvihill, M. J.; Ji, Q.-S.; Coate, H. R.; Cooke, A.; Dong, H.; Feng, L.; Foreman, K.; Rosenfeld-Franklin, M.; Honda, A.; Mak, G.; Mulvihill, K. M.; Nigro, A. I.; O'Connor, M.; Pirrit, C.; Steinig, A. G.; Siu, K.; Stolz, K. M.; Sun, Y.; Tavares, P. A. R.; Yao, Y.; Gibson, N. W. Bioorg. Med. Chem. 2008, 16, 1359.
27. Mulvihill, M. J.; Ji, Q.-S.; Werner, D.; Beck, P.; Cesario, C.; Cooke, A.; Cox, M.; Crew, A.; Dong, H.; Feng, L.; Foreman, K. W.; Mak, G.; Nigro, A.; O'Connor, M.; Saroglou, L.; Stolz, K. M.; Sujka, I.; Volk, B.; Weng, Q.; Wilkes, R. Bioorg. Med. Chem. Lett. 2007, 17, 1091.
28. Falcon, B. L.; Barr, S.; Gokhale, P. C.; Chou, J.; Fogarty, J.; Depeille, P.; Miglarese, M.; Epstein, D. M.; McDonald, D. M. Cancer Res. 2011, 71, 1.
29. 0 = median tumor volume of control group at time 0. Mean %TGI was calculated for the entire dosing period for each group. Significant anti-tumor activity is defined as mean %TGI >50%.