Optimization of diarylthiazole B-Raf inhibitors: Identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect

ChemMedChem

Volumn 10, Issue 2, 2015, Pages 276-295

  Pulici, M ^a   Traquandi, G ^a   Marchionni, C ^a   Modugno, M ^a   Lupi, R ^a   Amboldi, N ^a   Casale, E ^a   Colombo, N ^a   Corti, L ^a   Fasolini, M ^a   Gasparri, F ^a   Pastori, W ^a   Scolaro, A ^a   Donati, D ^a   Felder, E ^a   Galvani, A ^a   Isacchi, A ^a   Pesenti, E ^a   Ciomei, M ^a  

^a NERVIANO MEDICAL SCIENCES   (Italy)

Author keywords

Antitumor agents; B Raf inhibitors; Sulfonamides; Thiazoles

Indexed keywords

1 CYCLOPROPYLPIPERIDINE 4 CARBOTHIOAMIDE; 2,5 DIFLUORO N [2 FLUORO 3 [2 (1 METHYLPIPERIDIN 4 YL) 5 (PYRIDIN 4 YL) 1,3 THIAZOL 4 YL]PHENYL]BENZENESULFONAMIDE; 2,5 DIFLUORO N [2 FLUORO 3 [5 (PYRIDIN 4 YL) 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL]PHENYL]BENZENESULFONAMIDE; 2,5 DIFLUORO N[2 FLUORO 3 [5 (1 OXIDOPYRIDIN 4 YL) 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL]PHENYL]N(METHOXYMETHYL)BENZENESULFONAMIDE; 2,5 DIFLUORO N[2 FLUORO 3 [5 (2 METHYLPYRIDIN 4 YL) 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL]PHENYL]BENZENESULFONAMIDE; 2,5 DIFLUORO N[2 FLUORO 3 [5 [2 (METHYLAMINO)PYRIDIN 4 YL] 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL]PHENYL]BENZENESULFONAMIDE; 2,5 DIFLUORO N[3 [5 (PYRIDIN 4 YL) 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL]PHENYL]BENZENESULFONAMIDE; 2,6 DIFLUORO N[3 [5 (PYRIDIN 4 YL) 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL]PHENYL]BENZENESULFONAMIDE; ANTINEOPLASTIC AGENT; B RAF KINASE INHIBITOR; BENZYL 4 CARBAMOTHIOYLPIPERIDINE 1 CARBOXYLATE; DABRAFENIB; METHYL[1 [[4 [4 [3 [[(2,5 DIFLUOROPHENYL)SULFONYL]AMINO] 2 FLUOROPHENYL] 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 5 YL]PYRIDIN 2 YL]AMINO]PROPAN 2 YL]CARBAMATE; N [2 [[4 [4 [3 [[(2,5 DIFLUOROPHENYL)SULFONYL]AMINO] 2 FLUOROPHENYL] 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 5 YL]PYRIDIN 2 YL]AMINO]ETHYL]ACETAMIDE; N [3 (5 CHLORO 1H PYRROLO[2,3 B]PYRIDINE 3 CARBONYL) 2,4 DIFLUOROPHENYL]PROPANESULFONAMIDE; N [3 [5 [2 [[2 (DIMETHYLAMINO)ETHYL]AMINO]PYRIDIN 4 YL] 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N [4 [2 (1 CYCLOPROPYLPIPERIDIN 4 YL) 4 [3 [[(2,5 DIFLUOROPHENYL)SULFONYL]AMINO] 2 FLUOROPHENYL] 1,3 THIAZOL 5 YL]PYRIDIN 2 YL]ACETAMIDE; N[3 [2 (1 CYCLOPROPYLPIPERIDIN 4 YL) 5 (PYRIDIN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N[3 [2 (1 CYCLOPROPYLPIPERIDIN 4 YL) 5 [2 (METHYLAMINO)PYRIDIN 4 YL] 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZESULFONAMIDE; N[3 [2 (1,4 DIOXA 8 AZASPIRO[4.5]DEC 8 YL) 5 (PYRIDIN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N[3 [2 (4,4 DIFLUOROPIPERIDIN 1 YL) 5 (PYRIDIN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N[3 [2 (DIETHYLAMINO) 5 (PYRIDIN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N[3 [2 TERT BUTYL 5 (PYRIDIN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N[3 [5 (2 AMINOPYRIDIN 4 YL) 2 (1 CYCLOPROPYPYLPIPERIDIN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N[3 [5 (2 AMINOPYRIDIN 4 YL) 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; N[3 [5 (2 CHLOROPYRIDIN 4 YL) 2 (TETRAHYDRO 2H PYRAN 4 YL) 1,3 THIAZOL 4 YL] 2 FLUOROPHENYL] 2,5 DIFLUOROBENZENESULFONAMIDE; POTASSIUM CHANNEL HERG; TETRAHYDRO 2H PYRAN 4 CARBOTHIOAMIDE; UNCLASSIFIED DRUG; VEMURAFENIB; B RAF KINASE; ERG1 POTASSIUM CHANNEL; MAP2K1 PROTEIN, HUMAN; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; N-(4-(2-(1-CYCLOPROPYLPIPERIDIN-4-YL)-4-(3-(2,5-DIFLUOROBENZENESULFONYLAMINO)-2-FLUOROPHENYL)THIAZOL-5-YL)PYRIDIN-2-YL)ACETAMIDE; PROTEIN BINDING; PROTEIN KINASE INHIBITOR; SULFONAMIDE; THIAZOLE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG IDENTIFICATION; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROCESS OPTIMIZATION; VOLUME OF DISTRIBUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; BAGG ALBINO MOUSE; BINDING SITE; CELL PROLIFERATION; CHEMISTRY; DRUG EFFECTS; GENETICS; METABOLISM; NUDE MOUSE; ORAL DRUG ADMINISTRATION; PHOSPHORYLATION; PROTEIN TERTIARY STRUCTURE; TUMOR CELL LINE; XENOGRAFT;

ADMINISTRATION, ORAL; ANIMALS; ANTINEOPLASTIC AGENTS; BINDING SITES; CELL LINE, TUMOR; CELL PROLIFERATION; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; MAP KINASE KINASE 1; MICE; MICE, INBRED BALB C; MICE, NUDE; PHOSPHORYLATION; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PROTO-ONCOGENE PROTEINS B-RAF; SULFONAMIDES; THIAZOLES; TRANSPLANTATION, HETEROLOGOUS;

EID: 84921773577     PISSN: 18607179     EISSN: 18607187     Source Type: Journal    
DOI: 10.1002/cmdc.201402424     Document Type: Article

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