Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 12, 2012, Pages 4163-4168

  Finlay, M Raymond V ^a   Buttar, David ^a   Critchlow, Susan E ^a   Dishington, Allan P ^a   Fillery, Shaun M ^a   Fisher, Eric ^a   Glossop, Steve C ^a   Graham, Mark A ^a   Johnson, Trevor ^a   Lamont, Gillian M ^a   Mutton, Simon ^a   Perkins, Paula ^a   Pike, Kurt G ^a   Slater , Anthony M ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Enzyme; Inhibitor; Kinase; mTOR

Indexed keywords

HYDROGEN; INDOLE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PYRIMIDINE DERIVATIVE; SULFONYL MORPHOLINO PYRIMIDINE; UNCLASSIFIED DRUG;

ARTICLE; CELL ASSAY; DRUG SCREENING; DRUG STRUCTURE; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; HYDROGEN BOND; PHYSICAL CHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CELL LINE, TUMOR; HUMANS; HYDROGEN BONDING; INDOLES; INHIBITORY CONCENTRATION 50; MORPHOLINES; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES; TOR SERINE-THREONINE KINASES; UREA;

EID: 84861570789     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.04.036     Document Type: Article

References (21)

1. Pike, K. G.; Finlay, M. R. V.; Fillery, S. M.; Dishington, A. P. PCT Int. Appl. WO2007080382.
2. Finlay, M. R. V.; Morris, J.; Pike, K. G. PCT Int. Appl. WO2008023159.
3. K.A. Menear, S. Gomez, K. Malagu, C. Bailey, K. Blackburn, X.-L. Cockcroft, S. Ewen, A. Fundo, A. Le Gall, G. Hermann, L. Sebastian, M. Sunose, T. Presnot, E. Torode, I. Hickson, N.M.B. Martin, G.C.M. Smith, and K.G. Pike Bioorg. Med. Chem. Lett. 19 2009 5898
4. K. Malagu, H. Duggan, K. Menear, M. Hummersone, S. Gomez, C. Bailey, P. Edwards, J. Drzewiecki, F. Leroux, M.J. Quesada, G. Hermann, S. Maine, C.-A. Molyneaux, A. Le Gall, J. Pullen, I. Hickson, L. Smith, S. Maguire, N. Martin, G. Smith, and M. Pass Bioorg. Med. Chem. Lett. 19 2009 5950
5. D.J. Richard, J.C. Verheijen, and A. Zask Curr. Opin. Drug Discov. 13 2010 428
6. A. Roychowdhury, R. Sharma, and S. Kumar Future Med. Chem. 2 2010 1577
7. A. Zask, J.C. Verheijen, and D. Richard J. Expert Opin. Ther. Patents 7 2011 1109
8. A. Fasolo, and C. Sessa Expert Opin. Invest. Drugs 20 2011 381
9. C. Garcia-Echeverria Bioorg. Med. Chem. Lett. 20 2010 4308
10. A.L. Hopkins, C.R. Groom, and A. Alexander Drug Discovery Today 9 2004 430
11. P. Workman, P.A. Clarke, F.I. Raynaud, and R.L.M. van Montfort Cancer Res. 70 2010 2146
12. E.H. Walker, M.E. Pacold, O. Perisic, L. Stephens, P.T. Hawkins, M.P. Wymann, and R.L. Williams Mol. Cell 6 2000 909
13. L.S. Liebeskind, and J. Srogl Org. Lett. 4 2002 979
14. E.H. Walker, M.E. Pacold, O. Perisic, L. Stephens, P.T. Hawkins, M.P. Wymann, and R.L. Williams Mol. Cell 4 2000 909
15. E.H. Walker, O. Perisic, C. Ried, L. Stephens, and R.L. Williams Nature 402 1999 313
16. Figure 1 was generated using PyMOL: DeLano, W.L. The PyMOL Molecular Graphics System (2002), DeLano Scientific, San Carlos, CA, USA, http://www.pymol.org.
17. A. Zask, J. Kaplan, J.C. Verheijen, D.J. Richard, K. Curran, N. Brooijmans, E.M. Bennett, L. Toral-Barza, I. Hollander, S. Ayral-Kaloustian, and K. Yu J. Med. Chem. 52 2009 7942
18. P. Nowak, D.C. Cole, N. Brooijmans, M.G. Bursavich, K.J. Curran, J.W. Ellingboe, J.J. Gibbons, I. Hollander, Y.B. Hu, J. Kaplan, D.J. Malwitz, L. Toral-Barza, J.C. Verheijen, A. Zask, W.-G. Zhang, and K. Yu J. Med. Chem. 52 2009 7081
19. J.C. Verheijen, K. Yu, L. Toral-Barza, I. Hollander, and A. Zask Bioorg. Med. Chem. Lett. 20 2010 375
20. Castanedo, G.; Goldsmith, R.; Gunzner, J.; Heffron, T.; Malesky, K.; Mathieu, S.; Olivero, A.; Sutherlin, D. P.; Tsui, V.; Wang, S.; Weismann, C.; Zhu, B.-Y.; Dotson, J.; Folkes, A.; Shuttleworth, S.; Oxenford, S.; Hancox, T.; Bayliss, T. PCT Int. Appl. WO2007127183.
21. Bergeron, P.; Cohen, F.; Estrada, A.; Koehler, M. F. T.; Lau, K. H. L.; Cuong, L.; Lyssikatos, J. P.; Ortwine, D. F.; Pei, Z.; Zhao, X. PCT Int. Appl. WO2010014939.