Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N-Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)

Journal of Medicinal Chemistry

Volumn 58, Issue 15, 2015, Pages 6264-6282

  Basarab, Gregory S ^a   Doig, Peter ^a   Galullo, Vincent ^a   Kern, Gunther ^a   Kimzey, Amy ^a   Kutschke, Amy ^a   Newman, Joseph P ^a   Morningstar, Marshall ^a   Mueller, John ^a   Otterson, Linda ^a   Vishwanathan, Karthick ^a   Zhou, Fei ^a   Gowravaram, Madhusudhan ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

11 CHLOORO 2,4 DIMETHYL 8 (5 METHYL 2 OXOOXAZOLIDIN 3YL) 2,4,4A TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 11 CHLORO 2,4 DIMETHYL 8 (4 METHYL 2 OXOOXAZOLIDIN 3 YL) 2,4,4A,6 TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 11 CHLORO 8 [4 (METHOXYMETHYL) 2 OXO 1,3 OXAZOLIDIN 3YL] 2,4 DIMETHYL 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 CHLORO 8 [4 (METHOXYMETHYL) 2 OXOOXAZOLIDIN 3YL] 2,4 DIMETHYL 2,4,4A,6 TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 2',4',6' TRIOXO 2,2',3',4,4A,4',6,6' OCTAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDIN 8 YL) N,N DIMETHYL 2 OXOOXAZOLIDINE 4 CARBOXAMIDE; 11 FLUORO 2,4 DIMETHYL 8 (2 OXO 1,3 OXAZOLIDIN 3YL) 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 8 (2 OXOIMIDAZOLIDIN 1 YL) 2,4,4A,6 TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 8 (3 METHYL 2 OXOIMIDAZOLIDIN 1 YL) 2,4,4A,6 TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 8 (4 METHYL 2 OXO 1,3 OXAZOLIDIN 3 YL) 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO (1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 8 (4 METHYL 2 OXO 1,3 OXAZOLIDIN 3 YL) 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 8 (5 METHYL 2 OXO 1,3 OXAZOLIDIN 3 YL) 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO (1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 8 (5 METHYL 2 OXO 1,3 OXAZOLIDIN 3YL) 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 2,4 DIMETHYL 8 [2 OXO 4 PHENYL 1,3 OXAZOLIDIN 3YL] 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 8 [4 (HYDROXYMETHYL) 2 OXO 1,3 OXAZOLIDIN 3YL] 2,4 DIMETHYL 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 8 [4 (HYDROXYMETHYL) 2 OXOOXAZOLIDIN 3YL] 2,4 DIMETHYL 2,4,4A,6 TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,5 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 11 FLUORO 8 [4 (METHOXXYMETHYL) 2 OXO 1,3 OXAZOLIDIN 3YL] 2,4 DIMETHYL 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 11 FLUORO 8 [4 (METHOXYMETHYL) 2 OXO 1,3 OXAZOLIDIN 3YL] 2,4 DIMETHYL 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A][1,2] OXAZOLO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; 8 (4 CYCLOPROPYL 2 OXOOXAZOLIDIN 3 YL) 11 FLUORO 2,4 DIMETHYL 2,4,4A,6 TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 8 (4,5 DIMETHYL 2 OXOOXAZOLIDIN 3YL) 11 FLUORO 2,4 DIMETHYL 2,4,4A,6 TETRAHYDRO 1H,1'H SPIRO(ISOXAZOLO[4,5 G][1,4] OXAZINO[4,3 A]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(3'H) TRIONE; 8 [4 [(DIMETHYLAMINO)METHYL] 2 OXO 1,3 OXAZOLIDIN 3YL] 11 FLUORO 2,4 DIMETHYL 1,2,4,4A TETRAHYDRO 2'H,6H SPIRO(1,4 OXAZINO[4,3 A[1,2] OXAZINO[4,5 G]QUINOLINE 5,5' PYRIMIDINE) 2',4',6'(1'H,3'H) TRIONE; CIPROFLOXACIN; DNA TOPOISOMERASE (ATP HYDROLYSING); DNA TOPOISOMERASE IV; GYRASE INHIBITOR; OXAZOLIDINONE DERIVATIVE; SPIROPYRIMIDINETRIONE DERIVATIVE; UNCLASSIFIED DRUG; ISOXAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBACTERIAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG BIOAVAILABILITY; DRUG SYNTHESIS; ENZYME INHIBITION; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; MOUSE; NONHUMAN; STAPHYLOCOCCUS INFECTION; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; ANIMAL; CELL LINE; CHEMISTRY; DOG; DRUG DEVELOPMENT; HUMAN; MALE; RAT; X RAY CRYSTALLOGRAPHY;

ANIMALS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DOGS; DRUG DISCOVERY; HUMANS; ISOXAZOLES; MALE; OXAZOLIDINONES; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TOPOISOMERASE II INHIBITORS;

EID: 84939138677     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b00863     Document Type: Article

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