Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors

Journal of Medicinal Chemistry

Volumn 53, Issue 8, 2010, Pages 3169-3182

  Chen, Zecheng ^a   Venkatesan, Aranapakam M ^a   Dehnhardt, Christoph M ^a   Ayral Kaloustian, Semiramis ^a   Brooijmans, Natasja ^a   Mallon, Robert ^a   Feldberg, Larry ^a   Hollander, Irwin ^a   Lucas, Judy ^a   Yu, Ker ^a   Kong, Fangming ^a   Mansour, Tarek S ^a  

^a WYETH RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 [(4 METHYLPIPERAZIN 1 YL)CARBONYL]PHENYL 3 [4 [4 MORPHILIN 4 YL 7 (2,2,2 TRIFLUOROETHYL) 7H PYRROLO[2,3 D]PYRIMIDIN 2 YL]PHENYL]UREA; ACTIN; BIOLOGICAL MARKER; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MORPHOLINE DERIVATIVE; N [2 (DIMETHYLAMINO)ETHYL] N METHYL 4 [[[4 [4 MORPHOLIN 4 YL 7 (2,2,2 TRIFLUOROETHYL) 7H PYRROLO[2,3 D]PYRIMIDIN 2 YL]PHENYL]CARBAMOYL]AMINO]BENZAMIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE ALPHA; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN P110; PYRIMIDINE DERIVATIVE; S6 KINASE; SERINE; THREONINE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CANCER INHIBITION; CANCER MODEL; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; TUMOR XENOGRAFT;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; BENZAMIDES; CELL LINE, TUMOR; CELL PROLIFERATION; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; MICE, NUDE; MODELS, MOLECULAR; MORPHOLINES; PHENYLUREA COMPOUNDS; PHOSPHORYLATION; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS C-AKT; PYRIMIDINES; PYRROLES; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HETEROLOGOUS;

EID: 77951096315     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm901783v     Document Type: Article

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30. The homology model was built with Prime 1.6 (Prime, version 1.6; Schrodinger, LLC: New York, 2007) using an in-house X-ray structure of PI3K-g in complex with a related pyrazolopyrimidine (3IBE.pdb) as the template. Docking studies were performed using Glide, version 4.5, initially, and version 5.5 (Glide, version 5.5; Schrodinger, LLC: New York, 2009) more recently. Docking studies were either performed without constraints or with a hydrogen bonding constraint to the backbone-NH of Val851. Figure 2 was made using PyMOL (DeLano, W. L. The PyMOL Molecular Graphics System; DeLano Scientific LLC: Palo Alto, CA, 2008).