2-Arylureidophenyl-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines as highly potent and selective ATP competitive mTOR inhibitors: Optimization of human microsomal stability

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 8, 2010, Pages 2648-2653

  Verheijen, Jeroen C ^a   Richard, David J ^a   Curran, Kevin ^a   Kaplan, Joshua ^a   Yu, Ker ^a   Zask, Arie ^a  

^a WYETH RESEARCH   (United States)

Author keywords

Cancer; Kinase inhibitors; Microsomes; mTOR; Oncology; PI3K

Indexed keywords

ADENOSINE TRIPHOSPHATE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MORPHOLINE DERIVATIVE; PHOSPHATIDYLINOSITOL 3 KINASE; PIPERAZINE DERIVATIVE; TETRAHYDROPYRAN DERIVATIVE; TRIAZINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; GLIOBLASTOMA; GROWTH INHIBITION; HUMAN; HUMAN CELL; HUMAN TISSUE; LOW DRUG DOSE; MICROSOME; MOUSE; NONHUMAN; NUDE MOUSE; ONCOLOGY; SINGLE DRUG DOSE; TUMOR GROWTH; XENOGRAFT;

ANIMALS; HUMANS; INHIBITORY CONCENTRATION 50; MICE; MICROSOMES; TRANSPLANTATION, HETEROLOGOUS; TRIAZINES;

MURINAE;

EID: 77950031107     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.02.031     Document Type: Article

References (30)

1. For a recent review on rapamycin, the rapalogs and other mTOR inhibitors, see: Verheijen, J.; Yu, K.; Zask, A. in John E. Macor, editor: Ann. Rep. Med. Chem. 2008, 43, 189.
2. Carracedo A., and Pandolfi P.P. Oncogene 27 (2008) 5527
3. Choo A.Y., Yoon S.O., Kim S.G., Roux P.P., and Blenis J. Proc. Natl. Acad. Sci. U.S.A. 105 (2008) 17414
4. Guertin D.A., and Sabatini D.M. Sci. Signalling 2 (2009) 1
5. Sarbassov D.D., Ali S.M., Kim D.H., Guertin D.A., Latek R.R., Erdjument-Bromage H., Tempst P., and Sabatini D.M. Curr. Biol. 14 (2004) 1296
6. Sarbassov D.D., Guertin D.A., Ali S.M., and Sabatini D.M. Science 307 (2005) 1098
7. Feldman M.E., Apsel B., Uotila A., Loewith R., Knight Z.A., Ruggero D., and Shokat K.M. PLoS Biol. 7 (2009) 371
8. Thoreen C.C., Kang S.A., Chang J.W., Liu Q., Zhang J., Gao Y., Reichling L.J., Sim T., Sabatini D.M., and Gray N.S. J. Biol. Chem. 284 (2009) 8023
9. García-Martínez J.M., Moran J., Clarke R.G., Gray A., Cosulich S.C., Chresta C.M., and Alessi D.R. Biochem. J. 421 (2009) 29
10. Menear K.A., Gomez S., Malagu K., Bailey C., Blackburn K., Cockroft X.-L., Ewen S., Fundo A., Le Gall A., Hermann G., Sebastian L., Sunose M., Presnot T., Torode E., Hickson I., Martin N.M.B., Smith G.C.M., and Pike K.G. Bioorg. Med. Chem. Lett. 19 (2009) 5898
11. Malagu K., Duggan H., Menear K., Hummersone M., Gomez S., Bailey C., Edwards P., Drzewiecki J., Leroux F., Quesada M.J., Hermann G., Maine S., Molyneaux C.-A., Le Gall A., Pullen J., Hickson I., Smith L., Maguire S., Martin N., Smith G., and Pass M. Bioorg. Med. Chem. Lett. 19 (2009) 5950
12. Zask A., Verheijen J., Kaplan J., Curran K., Richard D., Brooijmans N., Lucas J., Toral-Barza L., Zhang W.-G., Hollander I., Gibbons J., Abraham R., Ayral-Kaloustian S., Mansour T., and Yu K. J. Med. Chem. 52 (2009) 5013
13. Nowak P., Brooijmans N., Cole D.C., Curran K.J., Ellingboe J., Gibbons J.J., Hu Y., Hollander I., Kaplan J., Malwitz D.J., Toral-Barza L., Verheijen J., Zask A., Zhang W.-G., and Yu K. J. Med. Chem. 52 (2009) 7081
14. Yu K., Toral-Barza L., Shi C., Zhang W.-G., Lucas J., Shor B., Kim J., Verheijen J., Curran K., Malwitz D.J., Cole D.C., Ellingboe J., Ayral-Kaloustian S., Mansour T.S., Gibbons J.J., Abraham R.T., Nowak P., and Zask A. Cancer Res. 69 (2009) 6232
15. Verheijen J.C., Richard D.J., Curran K., Kaplan J., Lefever M., Nowak P., Malwitz D.J., Brooijmans N., Toral-Barza L., Zhang W.-G., Hollander I., Ayral-Kaloustian S., Mansour T.S., Yu K., and Zask A. J. Med. Chem. 52 (2009) 8010
16. Verheijen J.C., Yu K., Toral-Barza L., Hollander I., and Zask A. Bioorg. Med. Chem. Lett. 20 (2010) 375
17. Richard D.J., Verheijen J.C., Curran K., Kaplan J., Brooijmans N., Toral-Barza L., Hollander I., Yu K., and Zask A. Bioorg. Med. Chem. Lett. 19 (2009) 6830
18. Curran K.J., Verheijen J.C., Kaplan J., Richard D.J., Toral-Barza L., Hollander I., Lucas J., Ayral-Kaloustian S., Yu K., and Zask A. Bioorg. Med. Chem. Lett. 20 (2010) 1440
19. Zask A., Verheijen J.C., Richard D.J., Kaplan J., Curran K., Toral-Barza L., Lucas J., Hollander I., and Yu K. Bioorg. Med. Chem. Lett. 20 (2010) 2644
20. Biological methods for determination of mTOR inhibition are described in:. Toral-Barza L., Zhang W.G., Lamison C., Larocque J., Gibbons J., and Yu K. Biochem. Biophys. Res. Commun. 332 (2005) 304
21. Biological methods for determination of inhibition of cellular proliferation are described in:. Yu K., Toral-Barza L., Discafani C., Zhang W.G., Skotnicki J., Frost P., and Gibbons J. Endocr.-Relat. Cancer 8 (2001) 249
22. Biological methods for determination of PI3K inhibition are described in:. Zask A., Kaplan J., Toral-Barza L., Hollander I., Young M., Tischler M., Gaydos C., Cinque M., Lucas J., and Yu K. J. Med. Chem. 51 (2008) 1319
23. Biological methods for determination of microsomal stability are described in:. Tsou H.-R., Liu X., Birnberg G., Kaplan J., Otteng M., Tran T., Kutterer K., Tang Z., Suayan R., Zask A., Ravi M., Bretz A., Grillo M., McGinnis J.P., Rabindran S.K., Ayral-Kaloustian S., and Mansour T.S. J. Med. Chem. 52 (2009) 2289
24. 1H NMR.
25. Richard D.J., Verheijen J.C., Yu K., and Zask A. Bioorg. Med. Chem. Lett. 20 (2010) 2654
26. Zask A., Kaplan J., Verheijen J., Richard D.J., Curran K., Brooijmans N., Bennett E., Toral-Barza L., Hollander I., Ayral-Kaloustian S., and Yu K. J. Med. Chem. 52 (2009) 7942
27. Kaplan J., Verheijen J.C., Brooijmans N., Toral-Barza L., Hollander I., Yu K., and Zask A. Bioorg. Med. Chem. Lett. 20 (2010) 640
28. Dehnhardt C.M., Venkatesan A.M., Delos Santos E., Chen Z., Santos O., Ayral-Kaloustian S., Brooijmans N., Mallon R., Hollander I., Feldberg L., Lucas J., Yu K., Gibbons J., Abraham R., and Mansour T.S. J. Med. Chem. (2009) 10.1021/jm9014982
29. The in-house kinase panel existed of the following kinases: ABL, Aurora B, CDK1/Cyclin B, CDK2/Cyclin A, CHK1, CK1 gamma1, ERK2, Fyn, GCK, HCK, LYN A, MK2, P38 alpha, PDGFR alpha, PKA, PKC alpha, PKC beta, ROCK 1, RSK1, SRC, VEGFR2.
30. In vivo methods for determination of biomarker inhibition and efficacy in nude mouse xenograft models have been described before; see Ref. 12.