Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3Kα and mTOR

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 15, 2012, Pages 5098-5103

  Le, Phuong T ^a   Cheng, Hengmiao ^a   Ninkovic, Sacha ^a   Plewe, Michael ^a   Huang, Xiaojun ^a   Wang, Hai ^a   Bagrodia, Shubha ^a   Sun, Shaoxian ^a   Knighton, Daniel R ^a   Lafleur Rogers, Caroline M ^a   Pannifer, Andrew ^b   Greasley, Samantha ^a   Dalvie, Deepak ^a   Zhang, Eric ^a  

^a PFIZER INC   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Cancer; Dual inhibitor; Kinase inhibitor; Methylpyrido pyrimidinone; mTOR; Physicochemical property based optimization; PI3K

Indexed keywords

4 METHYLPYRIDO PYRIMIDINONE; ERLOTINIB; GEFITINIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PF 4691502; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; SUNITINIB; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PHYSICAL CHEMISTRY; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HALF-LIFE; HUMANS; MICE; MICROSOMES, LIVER; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PYRIDONES; PYRIMIDINES; PYRIMIDINONES; PYRROLIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TOR SERINE-THREONINE KINASES;

EID: 84863982969     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.05.100     Document Type: Article

References (15)

1. J. Cui Expert. Opin. Ther. Patents 17 2007 1035
2. J.A. Engelman, J. Luo, and L.C. Cantley Nature 7 2006 606
3. D.A. Fruman, R.E. Myers, and L.C. Cantley Nat. Rev. Genet. 67 1998 481
4. R. Katso, K. Okkenhaug, K. Ahmadi, S. White, J. Timms, and M.D. Waterfield Annu. Rev. Cell Dev. Biol. 17 2001 615
5. Y. Samuels Science 304 2004 554
6. A.G. Bader, S. Kang, L. Zhao, and P.K. Vogt Nat. Rev. Cancer 5 2005 921
7. S.J. Isakoff Cancer Res. 65 2005 10992
8. Y. Samuels Cancer Cell 7 2005 561
9. I. Vivanco, and C.L. Sawyers Nat. Rev. Cancer 2 2002 489
10. A.S. Strimpakos, E.M. Karapanagiotou, W.W. Saif, and K.N. Syrigos Cancer Treat. Rev. 35 2009 148
11. D.D. Sarbassov, S.M. Ali, and D.M. Sabatini Curr. Opin. Cell Biol. 17 2005 596
12. H. Cheng, S. Bagrodia, S. Bailey, M. Edwards, J. Hoffman, Q. Hu, R. Kania, D.R. Knighton, M.A. Marx, S. Ninkovic, S. Sun, and E. Zhang MedChemComm 1 2010 139
13. M.E. Edwards, and D.A. Price J.E. Macor, M.C. Desai, Annual Reports in Medicinal Chemistry Vol. 45 2010 Elsevier 380 390
14. T.W. Johnson, K.R. Dress, and M. Edwards Bioorg. Med. Chem. Lett. 19 2009 5560
15. A.B. Dounay, and L.E. Overman Chem. Rev. 103 2003 2945