Structure-based design of tricyclic NF-κB inducing kinase (NIK) inhibitors that have high selectivity over phosphoinositide-3-kinase (PI3K)

Journal of Medicinal Chemistry

Volumn 60, Issue 2, 2017, Pages 627-640

  Castanedo, Georgette M ^a   Blaquiere, Nicole ^a   Beresini, Maureen ^a   Bravo, Brandon ^a   Brightbill, Hans ^a   Chen, Jacob ^a   Cui, Hai Feng ^b   Eigenbrot, Charles ^a   Everett, Christine ^a   Feng, Jianwen ^a   Godemann, Robert ^c   Gogol, Emily ^a   Hymowitz, Sarah ^a   Johnson, Adam ^a   Kayagaki, Nobuhiko ^a   Kohli, Pawan Bir ^a   Knüppel, Kathleen ^c   Kraemer, Joachim ^c   Krüger, Susan ^c   Loke, Pui ^d   McEwan, Paul ^d   Montalbetti, Christian ^d   Roberts, David A ^a   Smith, Myron ^d   Steinbacher, Stefan ^e   Sujatha Bhaskar, Swathi ^a   Takahashi, Ryan ^a   Wang, Xiaolu ^c   Wu, Lawren C ^a   Zhang, Yamin ^b   Staben, Steven T ^a   more..

^a GENENTECH INC   (United States)

^b PHARMARON   (United States)

^c EVOTEC AG   (Germany)

^d EVOTEC UK LTD   (United Kingdom)

^e PROTEROS BIOSTRUCTURES GMBH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

10 (3 HYDROXY 3 METHYLBUT 1 YN 1 YL) 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 10 (3 HYDROXY 3 METHYLBUT 1 YN 1 YL) 6 METHYL 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 10 [4 (DIMETHYLAMINO) 3 HYDROXY 3 METHYL 4 OXOBUT 1 YN 1 YL] 9 FLUORO 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 3 CYANO 9 FLUORO 10 (3 HYDROXY 3 METHYLBUT 1 YNYL) 5,6 DIHYDROIMIDAZO[1,2 D][1,4]BENZOXAZEPINE 2 CARBOXAMIDE; 3 CYCLOPROPYL 9 FLUORO 10 (3 HYDROXY 3 METHYLBUT 1 YNYL) 5,6 DIHYDROIMIDAZO[1,2 D][1,4]BENZOXAZEPINE 2 CARBOXAMIDE; 6,7 DIHYDROTHIENO[2',3':4,5]OXEPINO[3,2 B]PYRIDINE 2 CARBOXAMIDE; 8 FLUORO 9 (3 HYDROXY 3 METHYLBUT 1 YNYL) 4,5 DIHYDRO 6 OXA 1,3A DIAZABENZO[E]AZULENE 2 CARBOXYLIC ACID AMIDE; 9 (3 HYDROXY 3 METHYLBUT 1 YNYL) 4,5 DIHYDRO [1]BENZOXEPINO[5,4 D]THIAZOLE 2 CARBOXAMIDE; 9 FLUORO 10 (3 HYDROXY 3 (THIAZOL 2 YL)BUT 1 YN 1 YL) 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 (3 HYDROXY 3 METHYLBUT 1 YN 1 YL) 3 METHYL 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 (3 HYDROXY 3 METHYLBUT 1 YN 1 YL) 3 [(1 METHYL 1H PYRAZOL 5 YL)METHYL] 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 (3 HYDROXY 3 METHYLBUT 1 YNYL) 3 (1H PYRAZOL 4 YL) 5,6 DIHYDROIMIDAZO[1,2 D][1,4]BENZOXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 (3 HYDROXY 3 METHYLBUT 1 YNYL) N3 METHYL 5,6 DIHYDROIMIDAZO[1,2 D][1,4]BENZOXAZEPINE 2,3 DICARBOXAMIDE; 9 FLUORO 10 (3 HYDROXY 3 METHYLBUT 1 YNYL) N3,N3 DIMETHYL 5,6 DIHYDROIMIDAZO[1,2 D][1,4]BENZOXAZEPINE 2,3 DICARBOXAMIDE; 9 FLUORO 10 (4 FLUORO 3 HYDROXY 3 METHYLBUT 1 YN 1 YL 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 [(1 HYDROXYCYCLOBUTYL)ETHYNYL] 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 [(3 HYDROXY 1 METHYL 2 OXOPIPERIDIN 3 YL)ETHYNYL] 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 [(3 HYDROXY 1 METHYL 2 OXOPYRROLIDIN 3 YL)ETHYNYL] 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 [(3 HYDROXYOXETAN 3 YL)ETHYNYL] 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 [3 HYDROXY 3 (5 METHYLISOXAZOL 3 YL)BUT 1 YNYL] 5,6 DIHYDROIMIDAZO[1,2 D][1,4]BENZOXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 10 [3 HYDROXY 3 (PYRIDAZIN 3 YL)BUT 1 YN 1 YL] 5,6 DIHYDROBENZO[F]IMIDAZO[1,2 D][1,4]OXAZEPINE 2 CARBOXAMIDE; 9 FLUORO 3 [(2 FLUOROPHENYL)METHYL] 10 (3 HYDROXY 3 METHYLBUT 1 YNYL) 5,6 DIHYDROIMIDAZO[1,2 D][1,4]BENZOXAZEPINE 2 CARBOXAMIDE; ENZYME INHIBITOR; METHIONINE; NUCLEAR FACTOR KAPPA B INDUCING KINASE; NUCLEAR FACTOR KAPPA B INDUCING KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE; TRANSCRIPTION FACTOR RELA; UNCLASSIFIED DRUG; UNINDEXED DRUG; 10-(3-HYDROXY-3-(5-METHYLISOXAZOL-3-YL)BUT-1-YNYL)-N3-METHYL-5,6-DIHYDROIMIDAZO(1,2-D)(1,4)BENZOXAZEPINE-2,3-DICARBOXAMIDE; 10-FLUORO-9-(3-HYDROXY-3-(5-METHYL-1,2-OXAZOL-3-YL)BUT-1-YN-1-YL)-2,5-DIAZATETRACYCLO(11.1.1.0(2,6).0(7,12))PENTADECA-3,5,7(12),8,10-PENTAENE-4-CARBOXAMIDE; 2-(3-(2-(1-ISOPROPYL-3-METHYL-1H-1,2-4-TRIAZOL-5-YL)-5,6-DIHYDROBENZO(F)IMIDAZO(1,2-D)(1,4)OXAZEPIN-9-YL)-1H-PYRAZOL-1-YL)-2-METHYLPROPANAMIDE; FUSED HETEROCYCLIC RINGS; IMIDAZOLE DERIVATIVE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; ISOXAZOLE DERIVATIVE; NF-KAPPA B KINASE; OXAZEPINE DERIVATIVE; OXAZOLE DERIVATIVE; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE;

APPARENT PERMEABILITY; ARTICLE; BINDING AFFINITY; BINDING SITE; CONTROLLED STUDY; DRUG CLEARANCE; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME INHIBITION; HEK293 CELL LINE; HELA CELL LINE; HUMAN; LIPOPHILICITY; MOLECULAR WEIGHT; NONHUMAN; PROTEIN TRANSPORT; STRUCTURE ACTIVITY RELATION; VOLUME OF DISTRIBUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL NUCLEUS; CHEMISTRY; DOG; DRUG EFFECTS; METABOLISM; MOUSE; NUCLEOCYTOPLASMIC TRANSPORT; SIGNAL TRANSDUCTION; SYNTHESIS;

ACTIVE TRANSPORT, CELL NUCLEUS; ANIMALS; BINDING SITES; CELL NUCLEUS; DOGS; HEK293 CELLS; HELA CELLS; HETEROCYCLIC COMPOUNDS, 4 OR MORE RINGS; HETEROCYCLIC COMPOUNDS, BRIDGED-RING; HUMANS; IMIDAZOLES; ISOXAZOLES; MICE; NF-KAPPA B P50 SUBUNIT; NF-KAPPA B P52 SUBUNIT; OXAZEPINES; OXAZOLES; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION;

EID: 85010754776     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b01363     Document Type: Article

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