Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2S,3R)-3-(3,4- Difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]- diazepin-3-yl)butyramide by Use of an Asymmetric Ireland−Claisen Rearrangement
Novel benzodiazepine-containing γ-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of α-alkyl or aryl and β-hydroxy or hydroxymethyl substituents was shown to give highly potent compo...
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| Veröffentlicht in: | Journal of medicinal chemistry 2003-06, Vol.46 (12), p.2275-2278 |
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| container_issue | 12 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 46 |
| creator | Churcher, Ian Williams, Susie Kerrad, Sonia Harrison, Timothy Castro, José L Shearman, Mark S Lewis, Huw D Clarke, Earl E Wrigley, Jonathan D. J Beher, Dirk Tang, Yui S Liu, Wensheng |
| description | Novel benzodiazepine-containing γ-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of α-alkyl or aryl and β-hydroxy or hydroxymethyl substituents was shown to give highly potent compounds. In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC50 = 0.06nM). 34 could also be selectively methylated to give [3H]-28, which is of use in radioligand binding assays. |
| doi_str_mv | 10.1021/jm034058a |
| format | Article |
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In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC50 = 0.06nM). 34 could also be selectively methylated to give [3H]-28, which is of use in radioligand binding assays.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm034058a</identifier><identifier>PMID: 12773031</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amyloid beta-Peptides - antagonists & inhibitors ; Amyloid beta-Peptides - biosynthesis ; Amyloid Precursor Protein Secretases ; Aspartic Acid Endopeptidases ; Benzodiazepines - chemical synthesis ; Benzodiazepines - chemistry ; Benzodiazepines - pharmacology ; Benzodiazepinones - chemical synthesis ; Benzodiazepinones - chemistry ; Benzodiazepinones - pharmacology ; Drug Design ; Endopeptidases - metabolism ; Humans ; Isotope Labeling ; Ligands ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Structure-Activity Relationship ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 2003-06, Vol.46 (12), p.2275-2278</ispartof><rights>Copyright © 2003 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm034058a$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm034058a$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,27080,27928,27929,56742,56792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12773031$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Churcher, Ian</creatorcontrib><creatorcontrib>Williams, Susie</creatorcontrib><creatorcontrib>Kerrad, Sonia</creatorcontrib><creatorcontrib>Harrison, Timothy</creatorcontrib><creatorcontrib>Castro, José L</creatorcontrib><creatorcontrib>Shearman, Mark S</creatorcontrib><creatorcontrib>Lewis, Huw D</creatorcontrib><creatorcontrib>Clarke, Earl E</creatorcontrib><creatorcontrib>Wrigley, Jonathan D. J</creatorcontrib><creatorcontrib>Beher, Dirk</creatorcontrib><creatorcontrib>Tang, Yui S</creatorcontrib><creatorcontrib>Liu, Wensheng</creatorcontrib><title>Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2S,3R)-3-(3,4- Difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]- diazepin-3-yl)butyramide by Use of an Asymmetric Ireland−Claisen Rearrangement</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Novel benzodiazepine-containing γ-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of α-alkyl or aryl and β-hydroxy or hydroxymethyl substituents was shown to give highly potent compounds. In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC50 = 0.06nM). 34 could also be selectively methylated to give [3H]-28, which is of use in radioligand binding assays.</description><subject>Amyloid beta-Peptides - antagonists & inhibitors</subject><subject>Amyloid beta-Peptides - biosynthesis</subject><subject>Amyloid Precursor Protein Secretases</subject><subject>Aspartic Acid Endopeptidases</subject><subject>Benzodiazepines - chemical synthesis</subject><subject>Benzodiazepines - chemistry</subject><subject>Benzodiazepines - pharmacology</subject><subject>Benzodiazepinones - chemical synthesis</subject><subject>Benzodiazepinones - chemistry</subject><subject>Benzodiazepinones - pharmacology</subject><subject>Drug Design</subject><subject>Endopeptidases - metabolism</subject><subject>Humans</subject><subject>Isotope Labeling</subject><subject>Ligands</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVks1uEzEUhQcEoqGw4AWQN6BEygX_TSZlV1JKIiqIklYsqmrkmbnTOJ2xgz2RMl2xhC2vwnvwEH0SHNJWwhvr2p_OPT6-UfSC0TeMcvZ2WVMhaTxUD6MOizkFOaTyUdShlHPgAy72oqfeLymlgnHxJNpjPElEKDoP4Ai9vjREmYLMW9MsQumJLclYXy6qlkxtg6Yh79Fc20Kra1xpg-TPb5hj7rBRHsnELHSmG-v8u5vvP8nU4Uo51WhrtjpdPu-LWQ8EdEVfAjnSZbW2zq4WaNqqBxy6Ev4_CtSiLZzdtPAZul0x7wGDGptFWwXcbizEQHYw8L6AQv_DgY0h2_o8x4tz1pcXQO4ch-5BOFs3rVO1LpBkLTkL1oM_Zcihb-sg73ROJg6rEMXNj1-jSmmPhsxQOafMJdYhh2fR41JVHp_f7vvR2fGH09EYTr58nIwOT0CFYBtQCeYqK2WGlAteDpOsiBnywQEfJNkBZVwOsKQZzeOSlyilKCUmSshEZkKKJBf70eud7srZb2v0TVprn2MVvKFd-zQRYcWcBfDlLbjOaizSldO1cm1698EBgB2gfYOb-3vlrtJBIpI4PZ3O0_HxlM2-jj6lIvCvdrzKfbq0a2fCO1NG0-2gpfeDJv4CVgLEPA</recordid><startdate>20030605</startdate><enddate>20030605</enddate><creator>Churcher, Ian</creator><creator>Williams, Susie</creator><creator>Kerrad, Sonia</creator><creator>Harrison, Timothy</creator><creator>Castro, José L</creator><creator>Shearman, Mark S</creator><creator>Lewis, Huw D</creator><creator>Clarke, Earl E</creator><creator>Wrigley, Jonathan D. 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J</au><au>Beher, Dirk</au><au>Tang, Yui S</au><au>Liu, Wensheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2S,3R)-3-(3,4- Difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]- diazepin-3-yl)butyramide by Use of an Asymmetric Ireland−Claisen Rearrangement</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2003-06-05</date><risdate>2003</risdate><volume>46</volume><issue>12</issue><spage>2275</spage><epage>2278</epage><pages>2275-2278</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Novel benzodiazepine-containing γ-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of α-alkyl or aryl and β-hydroxy or hydroxymethyl substituents was shown to give highly potent compounds. In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC50 = 0.06nM). 34 could also be selectively methylated to give [3H]-28, which is of use in radioligand binding assays.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>12773031</pmid><doi>10.1021/jm034058a</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2003-06, Vol.46 (12), p.2275-2278 |
| issn | 0022-2623 1520-4804 |
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| source | MEDLINE; ACS Publications |
| subjects | Amyloid beta-Peptides - antagonists & inhibitors Amyloid beta-Peptides - biosynthesis Amyloid Precursor Protein Secretases Aspartic Acid Endopeptidases Benzodiazepines - chemical synthesis Benzodiazepines - chemistry Benzodiazepines - pharmacology Benzodiazepinones - chemical synthesis Benzodiazepinones - chemistry Benzodiazepinones - pharmacology Drug Design Endopeptidases - metabolism Humans Isotope Labeling Ligands Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Structure-Activity Relationship Tumor Cells, Cultured |
| title | Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2S,3R)-3-(3,4- Difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]- diazepin-3-yl)butyramide by Use of an Asymmetric Ireland−Claisen Rearrangement |
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