Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex

Journal of Medicinal Chemistry

Volumn 59, Issue 15, 2016, Pages 7125-7137

  Zhang, Xiaojun ^a   Glunz, Peter W ^a   Johnson, James A ^a   Jiang, Wen ^a   Jacutin Porte, Swanee ^a   Ladziata, Vladimir ^a   Zou, Yan ^a   Phillips, Monique S ^a   Wurtz, Nicholas R ^a   Parkhurst, Brandon ^a   Rendina, Alan R ^a   Harper, Timothy M ^a   Cheney, Daniel L ^a   Luettgen, Joseph M ^a   Wong, Pancras C ^a   Seiffert, Dietmar ^a   Wexler, Ruth R ^a   Priestley, E Scott ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [(1 AMINO 4 FLUOROISOQUINOLIN 6 YL)AMINO] 7 (CYCLOPROPANESULFONYL) 4,15,17 TRIMETHYL 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 3,12 DIONE; 2 [(1 AMINO 7 FLUOROISOQUINOLIN 6 YL)AMINO] 7 (CYCLOPROPANESULFONYL) 4,15,17 TRIMETHYL 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 3,12 DIONE; 2 [(1 AMINO 8 FLUOROISOQUINOLIN 6 YL)AMINO] 7 (CYCLOPROPANESULFONYL) 4,15,17 TRIMETHYL 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 3,12 DIONE; 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 3,12 DIONE; 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 7 CARBOXAMIDE; 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 7 (TRIFLUOROMETHOXY) 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 3,12 DIONE; 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 4,15,20 TRIMETHYL 7 (1 METHYL 1H PYRAZOL 5 YL) 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 3 DIONE; 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 7 (CYCLOPROPANE SULFONYL) 4,15,17 TRIMETHYL 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 3,12 DIONE; 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] N,N DIETHYL 14,15,17 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 7 CARBOXAMIDE; 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] N,N,4,15,17 PENTAMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 7 CARBOXAMIDE; 2 [[1 [BIS[(TERT BUTOXY)CARBONYL]AMINO]ISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO [14.2.2.16,10]HENICOSA 1(18),6,8,10(21),16,19 HEXAENE 7 CARBOXYLIC ACID; 4 FLUORO 3 METHOXY 6 NITRO 3,4 DIHYDROISOQUINOLIN 1(2H) ONE; 6 AMINO 1 (DI TERT BUTOXYCARBONYLAMINO) 7 FLUOROISOQUINOLINE; 6 AMINO 1 (DI TERT BUTOXYCARBONYLAMINO) 8 FLUOROISOQUINOLINE; BLOOD CLOTTING FACTOR 7A INHIBITOR; DIETHYL [2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAEN 7 YL]PHOSPHONATE; METHYL 2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAENE 7 CARBOXYLATE; METHYL 2 [(1 [BIS[(TERT BUTOXY)CARBONYL]AMINO] ISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10(21),16,19 HEXAENE 7 CARBOXYLATE; TERT BUTYL N (6 AMINO 4 FLUOROISOQUINOLIN 1 YL) N [(TERT BUTOXY)CARBONYL]CARBAMATE; TERT BUTYL N (6 [[[[[5 AMINO 2 (CYCLOPROPANESULFONYL)PHENYL] METHYL](METHYL)CARBAMOYL][[4(1 HYDROXYPROPAN 2 YL)3 METHYLPHENYL]]METHYL]AMINO] 8 FLUOROISOQUINOLIN 1 YL] N [(TERTBUTOXY) CARBONYL]CARBAMATE; TERT BUTYL N [6 [( 7 BROMO 4,15,20 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10(21),16,19 HEXAEN 2 YL]AMINO]ISOQUINOLIN 1 YL] N [(TERT BUTOXY) CARBONYL]CARBAMATE; TERT BUTYL N [6 [[[[(3 AMINOPHENYL)METHYL](METHYL)CARBAMOYL] [[4 (1 HYDROXYPROPAN 2 YL) 3 METHYLPHENYL]]METHYL]AMINO] ISOQUINOLIN 1 YL] N [(TERT BUTOXY)CARBONYL]CARBAMATE; TERT BUTYL N [6 [[[[[(5 AMINO 2 DIETHOXYPHOSPHORYL)PHENYL]METHYL](METHYL)CARBAMOYL] [[4 (1 HYDROXYPROPAN 2 YL) 3 METHYLPHENYL]]METHYL]AMINO]ISOQUINOLIN 1 YL] N [(TERT BUTOXY)CARBONYL]CARBAMATE; TERT BUTYL N [6 [[[[[5 AMINO 2 (1 METHYL 1H PYRAZOL 5 YL)PHENYL]METHYL](METHYL)CARBAMOYL] [[4 (1 HYDROXYPROPAN 2 YL) 3 METHYLPHENYL]]METHYL]AMINO]ISOQUINOLIN 1 YL] N [(TERT BUTOXY)CARBONYL]CARBAMATE; TERT BUTYL N [6 [[[[[5 AMINO 2 (CYCLOPROPANESULFONYL)PHENYL] METHYL](METHYL)CARBAMOYL]([4 (1 HYDROXYPROPAN 2 YL) 3 METHYLPHENYL]]METHYL]AMINO] 4 FLUOROISOQUINOLIN 1 YL] N [(TERTBUTOXY) CARBONYL]CARBAMATE; TERT BUTYL N [6 [[[[[5 AMINO 2 (CYCLOPROPANESULFONYL)PHENYL] METHYL](METHYL)CARBAMOYL]([4 (1 HYDROXYPROPAN 2 YL) 3 METHYLPHENYL]]METHYL]AMINO] 7 FLUOROISOQUINOLIN 1 YL] N [(TERTBUTOXY) CARBONYL]CARBAMATE; TERT BUTYL N [6 [[[[[5 AMINO 2 (TRIFLUOROMETHOXY)PHENYL]METHYL](METHYL)CARBAMOYL] [[4 (1 HYDROXYPROPAN 2 YL) 3 METHYLPHENYL]]METHYL]AMINO]ISOQUINOLIN 1 YL] N [(TERT BUTOXY)CARBONYL]CARBAMATE; THROMBOPLASTIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; [2 [(1 AMINOISOQUINOLIN 6 YL)AMINO] 4,15,17 TRIMETHYL 3,12 DIOXO 13 OXA 4,11 DIAZATRICYCLO[14.2.2.16,10]HENICOSA 1(18),6,8,10 (21),16,19 HEXAEN 7 YL](ETHOXY)PHOSPHINIC ACID; ANTICOAGULANT AGENT; BLOOD CLOTTING FACTOR 7A; MACROCYCLIC COMPOUND;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTICOAGULATION; ARTICLE; CAROTID ARTERY THROMBOSIS; DOG; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; FLUORINATION; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LIVER MICROSOME; METABOLIC STABILITY; MOLECULAR INTERACTION; NONHUMAN; PERMEABILITY; PROCESS OPTIMIZATION; RABBIT MODEL; RAT; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOAVAILABILITY; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; MALE; METABOLISM; MOLECULAR MODEL; NORMAL HUMAN; ORAL DRUG ADMINISTRATION; RABBITS AND HARES; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ANTICOAGULANTS; BIOLOGICAL AVAILABILITY; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; FACTOR VIIA; HEALTHY VOLUNTEERS; HUMANS; MACROCYCLIC COMPOUNDS; MALE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; RABBITS; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBOPLASTIN;

EID: 84982111759     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00469     Document Type: Article

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