Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153)

Journal of Medicinal Chemistry

Volumn 59, Issue 17, 2016, Pages 7801-7817

  Bradbury, Robert H ^a   Callis, Rowena ^a   Carr, Gregory R ^a   Chen, Huawei ^a   Clark, Edwin ^a   Feron, Lyman ^a   Glossop, Steve ^a   Graham, Mark A ^a   Hattersley, Maureen ^a   Jones, Chris ^a   Lamont, Scott G ^a   Ouvry, Gilles ^a   Patel, Anil ^a   Patel, Joe ^a   Rabow, Alfred A ^a   Roberts, Craig A ^a   Stokes, Stephen ^a   Stratton, Natalie ^a   Walker, Graeme E ^a   Ward, Lara ^a   Whalley, David ^a   Whittaker, David ^a   Wrigley, Gail ^a   Waring, Michael J ^a,b   more..

^a ASTRAZENECA   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1 METHYL 4 [2 [4 [1 [3 (TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOXY]ETHYL]PIPERAZIN 2 ONE; 1 [4 [2 [4 [1 [3 (TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOXY]ETHYL]PIPERAZIN 1 YL]ETHANONE; 1,3 DIMETHYL 4 [2 [4 (PIPERIDIN 4 YL)PHENOXY]ETHYL]PIPERAZIN 2 ONE DIHYDROCHLORIDE; 1,3 DIMETHYL 4 [2 [4 [1 (3 METHYLTHIO[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL]PIPERAZIN 2 ONE; 1,3 DIMETHYL 4 [2 [4 [1 (3 METHYL[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL]PIPERAZIN 2 ONE; 1,3 DIMETHYL 4 [2 [4 [1 [3 (TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOXY]ETHYL]PIPERAZIN 2 ONE; 1,4 [2 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL] 3,5 DIMETHYLPIPERAZIN 1 YL]ETHANONE; 2 [4 [1 [3 (TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOXY]ETHANOL; 2 [4 [1 [3 (TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOXY]ETHYLMETHANESULFONATE; 4 METHYL 1 [2 [4 [1 [3 (TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOXY]ETHYL]PIPERAZIN 2 ONE; 4 [1 [3 (TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOL; 4 [1 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENYL]AZETIDIN 3 YL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [1 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENYL]PIPERIDIN 4 YL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [2 [4 [1 (3 CHLORO[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [2 [4 [1 (3 METHOXY [1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL) 4 PIPERIDYL]PHENOXY]ETHYL] 1,3 DIMETHYL PIPERAZIN 2 ONE; 4 [2 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [2 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL] 1,3,5 TRIMETHYLPIPERAZIN 2 ONE; 4 [2 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL] 2,6 DIMETHYLPIPERAZIN 1 YL]ETHANONE; 4 [2 [4 [1 ([1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]ETHYL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [2 [4 [1 [3 (DIMETHYLAMINO)[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL]PIPERIDIN 4 YL]PHENOXY]ETHYL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [3 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]PROPYL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENETHYL] 1,3 DIMETHYLPIPERAZIN 2 ONE; 4 [4 [4 [1 (3 METHOXY[1,2,4]TRIAZOLO[4,3 B]PYRIDAZIN 6 YL)PIPERIDIN 4 YL]PHENOXY]BUTYL] 1,3 DIMETHYLPIPERAZIN 2 ONE; ANTINEOPLASTIC AGENT; BROMODOMAIN INHIBITOR; MYC PROTEIN; TERT BUTYL 4 (4 HYDROXYPHENYL)PIPERIDINE 1 CARBOXYLATE; TERT BUTYL 4 [4 (2 CHLOROETHOXY)PHENYL]PIPERIDINE 1 CARBOXYLATE; TRIAZOLOPYRIDAZINE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; AZD5153; BRD4 PROTEIN, HUMAN; FUSED HETEROCYCLIC RINGS; NUCLEAR PROTEIN; PIPERAZINE DERIVATIVE; TRANSCRIPTION FACTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DOWN REGULATION; DRUG BINDING; DRUG CLEARANCE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SOLUBILITY; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PHARMACODYNAMIC PARAMETERS; PHARMACOKINETIC PARAMETERS; PHYSICAL CHEMISTRY; PLASMA CONCENTRATION-TIME CURVE; PROCESS OPTIMIZATION; RAT; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; TUMOR XENOGRAFT; ANIMAL; ANTAGONISTS AND INHIBITORS; CACO-2 CELL LINE; CANCER TRANSPLANTATION; CHEMISTRY; DOG; DRUG EFFECTS; FEMALE; LIVER CELL; METABOLISM; PROTEIN CONFORMATION; SCID MOUSE; STEREOISOMERISM; X RAY CRYSTALLOGRAPHY; XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; CACO-2 CELLS; CRYSTALLOGRAPHY, X-RAY; DOGS; FEMALE; HEPATOCYTES; HETEROCYCLIC COMPOUNDS, 2-RING; HETEROGRAFTS; HUMANS; MICE, SCID; NEOPLASM TRANSPLANTATION; NUCLEAR PROTEINS; PIPERAZINES; PROTEIN CONFORMATION; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTION FACTORS;

EID: 84986294614     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00070     Document Type: Article

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