Discovery of (2 S)-8-[(3 R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2 H -pyrimido[1,2- a ]pyrimidin-6-one: A novel potent and selective inhibitor of Vps34 for the treatment of solid tumors

Journal of Medicinal Chemistry

Volumn 58, Issue 1, 2015, Pages 376-400

  Pasquier, Benoit ^a   El Ahmad, Youssef ^a   Filoche Rommé, Bruno ^a   Dureuil, Christine ^a   Fassy, Florence ^a   Abecassis, Pierre Yves ^a   Mathieu, Magali ^a   Bertrand, Thomas ^a   Benard, Tsiala ^a   Barrière, Cédric ^a   El Batti, Samira ^a   Letallec, Jean Philippe ^a   Sonnefraud, Véronique ^a   Brollo, Maurice ^a   Delbarre, Laurence ^a   Loyau, Véronique ^a   Pilorge, Fabienne ^a   Bertin, Luc ^a   Richepin, Patrick ^a   Arigon, Jérôme ^a   Labrosse, Jean Robert ^a   Clément, Jacques ^a   Durand, Florence ^a   Combet, Romain ^a   Perraut, Pierre ^a   Leroy, Vincent ^a   Gay, Frédéric ^a   Lefrançois, Dominique ^a   Bretin, François ^a   Marquette, Jean Pierre ^a   Michot, Nadine ^a   Caron, Anne ^a   Castell, Christelle ^a   Schio, Laurent ^a   McCort, Gary ^a   Goulaouic, Hélène ^a   Garcia Echeverria, Carlos ^a   Ronan, Baptiste ^a   more..

^a SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

(2) 1 (2 ISOPROPOXYETHYL) 2 METHYL 8 MORPHOLINO 2 (TRIFLUOROMETHYL) 3,4 DIHYDROPYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 (ISOXAZOL 3 YLMETHYL) 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 (ISOXAZOL 5 YLMETHYL) 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(2 FLUORO 4 PYRIDYL)METHYL] 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(5 CHLORO 2 THIENYL)METHYL] 8 (3 OXA 8 AZABICYCLO [321]OCTAN 8 YL) 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(5 CHLORO 2 THIENYL)METHYL] 8 (8 OXA 3 AZABICYCLO [321]OCTAN 3 YL) 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(5 CHLORO 2 THIENYL)METHYL] 8 MORPHOLINO 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(5 CHLORO 2 THIENYL)METHYL] 8 [(1,4) 2 OXA 5 AZABICYCLO [221]HEPTAN 5 YL) 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(5 CHLORO 2 THIENYL)METHYL] 8 [(3) 3 METHYLMORPHOLIN 4 YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(5 CHLORO 2 THIENYL)METHYL] 8 [(3,5) 3,5 DIMETHYL MORPHOLINO 4 YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 1 [(5 CHLORO 3 PYRIDYL)METHYL] 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 7 FLUORO 1 (2 HYDROXY 2 METHYL PROPYL) 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 7 FLUORO 1 (2 METHOXY 4 PYRIDYL) 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 7 FLUORO 1 (2 METHOXYETHYL) 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 7 FLUORO 1 (ISOXAZOL 3 YLMETHYL) 8 [(3) 3 METHYLMORPHOLIN 4 YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 7 FLUORO 1 (ISOXAZOL 5 YLMETHYL) 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 7 FLUORO 1 [(2 FLUORO 4 PYRIDYL)METHYL] 8 [(3) 3 METHYLMORPHOLIN 4YL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 7 FLUORO 8 [(3) 3 METHYLMORPHOLIN 4 YL] 1 [2 OXO 2 (3 PYRIDYL)ETHYL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 8 [(3) 3 METHYLMORPHOLIN 4 YL] 1 (3 METHYL 2 OXOBUTYL) 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 8 [(3) 3 METHYLMORPHOLIN 4 YL] 1 [2 OXO 2 (2 PYRIDYL)ETHYL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; (2) 8 [(3) 3 METHYLMORPHOLIN 4 YL] 1 [2 OXO 2 (3 PYRIDYL)ETHYL] 2 (TRIFLUOROMETHYL) 3,4 DIHYDRO 2H PYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; 1 (2 ISOPROPOXYETHYL) 2,2 DIMETHYL 8 MORPHOLINO 3,4 DIHYDROPYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; 1 [(2) 2 HYDROXY 2 PHENYLETHYL] 2,2 DIMETHYL 8 MORPHOLINO 3,4 DIHYDROPYRIMIDO[1,2 A]PYRIMIDIN 6 ONE; 1 [(2) 2 HYDROXY 2 PHENYLETHYL] 8 MORPHOLINO SPIRO[3,4 DIHYDROPYRIMIDO[1,2 A]PYRIMIDINE 2,1' CYCLOPROPANE] 6 ONE; AZD 6482; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PYRIMIDINONE DERIVATIVE; TETRAHYDROPYRIMIDOPYRIMIDINONE DERIVATIVE; TGX 221; UNCLASSIFIED DRUG; UNINDEXED DRUG; 8-(3-METHYLMORPHOLIN-4-YL)-1-(3-METHYL-2-OXOBUTYL)-2-(TRIFLUOROMETHYL)-3,4-DIHYDRO-2H-PYRIMIDO(1,2-A)PYRIMIDIN-6-ONE; ANTINEOPLASTIC AGENT; ENZYME INHIBITOR; FUSED HETEROCYCLIC RINGS; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BINDING;

ACUTE DRUG ADMINISTRATION; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; FEMALE; HUMAN; HUMAN CELL; HUMAN TISSUE; IN VIVO STUDY; MALE; MEDICINAL CHEMISTRY; MOUSE; NONHUMAN; SOLID TUMOR; X RAY ANALYSIS; X RAY CRYSTAL STRUCTURE; AMINO ACID SEQUENCE; ANIMAL; ANTAGONISTS AND INHIBITORS; CACO 2 CELL LINE; CHEMICAL MODEL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG SCREENING; HELA CELL LINE; METABOLISM; MOLECULAR GENETICS; NEOPLASMS; PATHOLOGY; PROTEIN TERTIARY STRUCTURE; SCID MOUSE; SEQUENCE HOMOLOGY; SPRAGUE DAWLEY RAT; THERMODYNAMICS; TUMOR CELL LINE; X RAY CRYSTALLOGRAPHY;

AMINO ACID SEQUENCE; ANIMALS; ANTINEOPLASTIC AGENTS; AREA UNDER CURVE; BICYCLO COMPOUNDS, HETEROCYCLIC; CACO-2 CELLS; CELL LINE, TUMOR; CLASS III PHOSPHATIDYLINOSITOL 3-KINASES; CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; ENZYME INHIBITORS; HELA CELLS; HUMANS; MALE; MICE, SCID; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; NEOPLASMS; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; PYRIMIDINONES; RATS, SPRAGUE-DAWLEY; SEQUENCE HOMOLOGY, AMINO ACID; THERMODYNAMICS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84920842452     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5013352     Document Type: Article

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