Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase

Journal of Medicinal Chemistry

Volumn 59, Issue 10, 2016, Pages 4948-4964

  Huang, Wei Sheng ^a   Liu, Shuangying ^a   Zou, Dong ^a   Thomas, Mathew ^a   Wang, Yihan ^a   Zhou, Tianjun ^a   Romero, Jan ^a   Kohlmann, Anna ^a   Li, Feng ^a   Qi, Jiwei ^a   Cai, Lisi ^a   Dwight, Timothy A ^a   Xu, Yongjin ^a   Xu, Rongsong ^a   Dodd, Rory ^a   Toms, Angela ^a   Parillon, Lois ^a   Lu, Xiaohui ^a   Anjum, Rana ^a   Zhang, Sen ^a   Wang, Frank ^a   Keats, Jeffrey ^a   Wardwell, Scott D ^a   Ning, Yaoyu ^a   Xu, Qihong ^a   Moran, Lauren E ^a   Mohemmad, Qurish K ^a   Jang, Hyun Gyung ^a   Clackson, Tim ^a   Narasimhan, Narayana I ^a   Rivera, Victor M ^a   Zhu, Xiaotian ^a   Dalgarno, David ^a   Shakespeare, William C ^a   more..

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(2 ((2 ((4 (4 (AZETIDIN 1 YL METHYL)PIPERADIN 1 YL) 2 METHOXYPHENYL)AMINO) 5 CHLOROPYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHOXYPHENYL)AMINO) 5 CHLOROPYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 ((1 METHYLPIPERIDIN 4 YL)OXY)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 ((1 METHYLPYRROLIDIN 3 YL)OXY)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (3 (PIPERIDIN 1 YL)PYRROLIDIN 1 YL)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (3 (PYRROLIDIN 1 YL)PROPOXY)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (4 (1 METHYLPIPERIDIN 4 YL)PIPERAZIN 1 YL)PHENYL)AMINO)PHENYL)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (4 (4 METHYL 1,4 DIAZEPAN 1 YL)PIPERIDIN 1 YL)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (4 (PYRROLIDIN 1 YL)PIPERIDIN 1 YL)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (4 METHYL 1,4 DIAZEPAN 1 YL)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (4 METHYLPIPERAZIN 1 YL)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 (4 MORPHOLINOPIPERIDIN 1 YL)PHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((2 METHOXY 4 MORPHOLINOPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYL PHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((4 (3 (DIMETHYLAMINO)PYRROLIDIN 1 YL) 2 METHOXYPHENY)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL) DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((4 (3 (DIMETHYLAMINO)PYRROLIDIN 1 YL) 2 METHOXYPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((4 (4 (2 HYDROXYETHYL)PIPERAZIN 1 YL) 2 METHOXYPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((4 (4 (DIMETHYLAMINO)PIPERIDIN 1 YL) 2 METHOXYPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (2 ((5 CHLORO 2 ((4 (4 HYDROXYPIPERIDIN 1 YL) 2 METHOXYPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPINE OXIDE; (2 ((5 CHLORO 2 ((4 (DIMETHYLPHOSPHORYL) 2 METHOXYPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)DIMETHYLPHOSPHINE OXIDE; (4 ((5 CHLORO 4 ((2 (ISOPROPYLSULFONYL)PHENYL)AMINO)PYRIMIDIN 2 YL)AMINO) 3 METHOXYPHENYL)DIMETHYLPHOSPHINE OXIDE; (4 ((5 CHLORO 4 ((2 (METHYLSULFONYL)PHENYL)AMINO)PYRIMIDIN 2 YL)AMINO) 3 METHOXYPHENYL)DIMETHYLPHOSPHINE OXIDE; (4 ((5 CHLORO 4 ((2 METHOXYPHENYL)AMINO)PYRIMIDIN 2 YL)AMINO) 3 METHOXYPHENYL)DIMETHYLPHOSPHINE OXIDE; 1 (2 ((5 CHLORO 2 ((4 (DIMETHYLPHOSPHORYL) 2 METHOXYPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)PHENYL)ETHAN 1 ONE; 1 (4 (4 ((5 CHLORO 4 ((2 (DIMETHYLPHOSPHORYL)PHENYL)AMINO)PYRIMIDIN 2 YL)AMINO) 3 METHOXY PHENYL)PIPERAZIN 1 YL)ETHAN 1 ONE; 2 ((5 CHLORO 2 ((4 (DIMETHYLPHOSPHORYL) 2 METHOXYPHENYL)AMINO)PYRIMIDIN 4 YL)AMINO)BENZAMIDE; 2 (4 (4 ((5 CHLORO 4 ((2 (DIMETHYLPHOSPHORYL)PHENYL)AMINO)PYRIMIDIN 2 YL)AMINO) 3 METHOXY PHENYL)PIPERAZIN 1 YL)N METHYLACETAMIDE; 5 CHLORO N4 (2 (ISOPROPYLSULFONYL)PHENYL) N2 (2 METHOXYPHENYL)PYRIMIDINE 2,4 DIAMINE; ANTINEOPLASTIC AGENT; BRIGATINIB; CRIZOTINIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; ANAPLASTIC LYMPHOMA KINASE; ORGANOPHOSPHORUS COMPOUND; PHOSPHINE; PHOSPHINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE; PYRIMIDINE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CANCER CELL LINE; CANCER INHIBITION; CELL VIABILITY; CONTROLLED STUDY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME ACTIVITY; FEMALE; HYDROGEN BOND; IC50; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; TUMOR XENOGRAFT; ANIMAL; ANTAGONISTS AND INHIBITORS; CARCINOMA, NON-SMALL-CELL LUNG; CELL PROLIFERATION; CELL SURVIVAL; CHEMISTRY; CONFORMATION; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG EFFECTS; DRUG SCREENING; ENZYMOLOGY; GENETICS; HUMAN; LUNG NEOPLASMS; METABOLISM; NEOPLASMS, EXPERIMENTAL; ORAL DRUG ADMINISTRATION; PATHOLOGY; RAT; SCID MOUSE; TUMOR CELL LINE;

ADMINISTRATION, ORAL; ANIMALS; ANTINEOPLASTIC AGENTS; CARCINOMA, NON-SMALL-CELL LUNG; CELL LINE, TUMOR; CELL PROLIFERATION; CELL SURVIVAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HUMANS; LUNG NEOPLASMS; MICE; MICE, SCID; MOLECULAR CONFORMATION; NEOPLASMS, EXPERIMENTAL; ORGANOPHOSPHORUS COMPOUNDS; PHOSPHINES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; RATS; RECEPTOR PROTEIN-TYROSINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84971596896     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00306     Document Type: Article

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