Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

Journal of Medicinal Chemistry

Volumn 59, Issue 7, 2016, Pages 3231-3248

  Mandal, Mihirbaran ^a   Wu, Yusheng ^a   Misiaszek, Jeffrey ^a   Li, Guoqing ^a   Buevich, Alexei ^a   Caldwell, John P ^a   Liu, Xiaoxiang ^a   Mazzola, Robert D ^a   Orth, Peter ^a   Strickland, Corey ^a   Voigt, Johannes ^a   Wang, Hongwu ^a   Zhu, Zhaoning ^a   Chen, Xia ^a   Grzelak, Michael ^a   Hyde, Lynn A ^a   Kuvelkar, Reshma ^a   Leach, Prescott T ^a   Terracina, Giuseppe ^a   Zhang, Lili ^a   Zhang, Qi ^a   Michener, Maria S ^a   Smith, Brad ^a   Cox, Kathleen ^b   Grotz, Diane ^b   Favreau, Leonard ^b   Mitra, Kaushik ^b   Kazakevich, Irina ^a   McKittrick, Brian A ^a   Greenlee, William ^a   Kennedy, Matthew E ^a   Parker, Eric M ^a   Cumming, Jared N ^a   Stamford, Andrew W ^a   more..

^a Department of Global Chemistry ^*  (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(4A,7A) 7A (5 CHLOROTHIOPHEN 2 YL) 6 (4 ETHYL 5 FLUORO 6 METHOXYPYRIMIDIN 2 YL) 2 IMINO 3 METHYLHEXAHYDRO 1H PYRROLO[3,4 D]PYRIMIDIN 4(4AH) ONE; (4A,7A) 7A (5 CHLOROTHIOPHEN 2 YL) 6 (5 FLUORO 4 METHOXY 6 METHYLPYRIMIDIN 2 YL) 2 IMINO 3 METHYLOCTAHYDRO 1H PYRROLO[3,4 D]PYRIMIDIN 4(4AH) ONE; (4A,7A) 7A (5 CHLOROTHIOPHEN 2 YL) 6 (5 FLUORO 4 METHOXY 6 PROPYLPYRIMIDIN 2 YL) 2 IMINO 3 METHYLHEXAHYDRO 1H PYRROLO[3,4 D]PYRIMIDIN 4(4AH) ONE; 5 [(4A,7A) 6 (4 ETHOXY 5 FLUORO 6 METHYLPYRIMIDIN 2 YL) 2 IMINO 3 METHYL 4 OXOOCTAHYDRO 1H PYROLO[3,4 D]PYRIMIDIN 7A YL] THIOPHENE 2 CARBONITRILE; 5 [(4A,7A) 6 (5 FLUORO 4 METHOXY 6 METHYLPYRIMIDIN 2 YL) 2 IMINO 3 METHYL 4 OXOOCTAHYDRO 1H PYROLO[3,4 D]PYRIMIDIN 7A YL] THIOPHENE 2 CARBONITRILE; 5 [(4A,7A) 6 (5 FLUORO 4 METHOXYPYRIMIDIN 2 YL) 2 IMINO 3 METHYL 4 OXOOCTAHYDRO 1H PYROLO[3,4 D]PYRIMIDIN 7A YL] THIOPHENE 2 CARBONITRILE; 5 [(4A,7A) 6 [5 FLUORO 4 METHYL 6 (METHYLTHIO)PYRIMIDIN 2 YL] 2 IMINO 3 METHYL 4 OXOOCTAHYDRO 1H PYROLO[3,4 D]PYRIMIDIN 7A YL] THIOPHENE 2 CARBONITRILE; 7A (2,4 DIFLUOROPHENYL) 6 (5 FLUORO 4 METHOXY 6 METHYLPYRIMIDIN 2 YL) 2 IMINO 3 METHYLOCTAHYDRO 4H PYRROLO[3,4 D]PYRIMIDIN 4 ONE; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; BETA SECRETASE 1; BETA SECRETASE INHIBITOR; CYTOCHROME P450 3A4; THIOPHENE DERIVATIVE; UNCLASSIFIED DRUG; AMYLOID PRECURSOR PROTEIN; ENZYME INHIBITOR; HETEROCYCLIC COMPOUND; IMINE; SECRETASE;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; BRAIN CORTEX; CEREBROSPINAL FLUID; CONTROLLED STUDY; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG PENETRATION; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; IC50; MACACA FASCICULARIS; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PROTEIN CLEAVAGE; RAT; STRUCTURE ACTIVITY RELATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; METABOLISM;

AMYLOID BETA-PEPTIDES; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; CEREBRAL CORTEX; DRUG DESIGN; ENZYME INHIBITORS; HETEROCYCLIC COMPOUNDS; IMINES; MACACA FASCICULARIS; MOLECULAR STRUCTURE; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84966262735     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01995     Document Type: Article

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