Design, synthesis, and biological evaluation of 2-Oxo-3,4- dihydropyrimido[4,5-d]pyrimidinyl derivatives as new irreversible epidermal growth factor receptor inhibitors with improved pharmacokinetic properties

Journal of Medicinal Chemistry

Volumn 56, Issue 21, 2013, Pages 8803-8813

  Xu, Shilin ^a,b   Xu, Tianfeng ^a,b   Zhang, Lianwen ^a   Zhang, Zhang ^a   Luo, Jinfeng ^a   Liu, Yingxue ^a   Lu, Xiaoyun ^a   Tu, Zhengchao ^a   Ren, Xiaomei ^a   Ding, Ke ^a  

^a GUANGZHOU INSTITUTES OF BIOMEDICINE AND HEALTH   (China)

^b UNIVERSITY OF CHINESE ACADEMY OF SCIENCES   (China)

Author keywords

[No Author keywords available]

Indexed keywords

1 (1 ACRYLOYLPIPERIDIN 3 YL) 3 BENZYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPIPERIDIN 4 YL) 3 BENZYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 3 BENZYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 3 CYCLOHEXYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 3 CYCLOPENTYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 3 ISOPROPYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 3 PHENYL 7 (PHENYLAMINO) 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 METHYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [3 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [3 CHLORO 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [3 FLUORO 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [3 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [3 METHYL 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [4 (1 METHYLPIPERAZIN 4 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [4 (4 METHYLPIPERAZIN 1 YL) 3 (TRIFLUOROMETHYL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 1 (1 ACRYLOYLPYRROLIDIN 3 YL) 7 [4 [2 (4 METHYLPIPERAZIN 1 YL)ETHYL]PHENYLAMINO] 3 PHENYL 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 2(1H) ONE; 2 OXO 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDINYL DERIVATIVE; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; GEFITINIB; N [2 [3 BENZYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL) PHENYLAMINO] 2 OXO 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 1(2H) YL]ETHYL]ACRYLAMIDE; N [4 [3 BENZYL 7 [2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO] 2 OXO 3,4 DIHYDROPYRIMIDO[4,5 D]PYRIMIDIN 1(2H) YL]CYCLOHEXYL]ACRYLAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CANCER CELL; CANCER INHIBITION; CELL PROLIFERATION; CONTROLLED STUDY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG SCREENING; DRUG SOLUBILITY; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; LUNG NON SMALL CELL CANCER; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PROTEIN PHOSPHORYLATION; RAT; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CELL PROLIFERATION; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; HETEROCYCLIC COMPOUNDS, 2-RING; HUMANS; MALE; MICE; MICE, SCID; MOLECULAR STRUCTURE; PYRIMIDINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, EPIDERMAL GROWTH FACTOR; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; THERMODYNAMICS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84887920359     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4012388     Document Type: Article

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