Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid
A series of potent hydroxyethyl amine (HEA) derived inhibitors of β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased ora...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-11, Vol.55 (21), p.9009-9024 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 55 |
| creator | Weiss, Matthew M Williamson, Toni Babu-Khan, Safura Bartberger, Michael D Brown, James Chen, Kui Cheng, Yuan Citron, Martin Croghan, Michael D Dineen, Thomas A Esmay, Joel Graceffa, Russell F Harried, Scott S Hickman, Dean Hitchcock, Stephen A Horne, Daniel B Huang, Hongbing Imbeah-Ampiah, Ronke Judd, Ted Kaller, Matthew R Kreiman, Charles R La, Daniel S Li, Vivian Lopez, Patricia Louie, Steven Monenschein, Holger Nguyen, Thomas T Pennington, Lewis D Rattan, Claire San Miguel, Tisha Sickmier, E.Allen Wahl, Robert C Wen, Paul H Wood, Stephen Xue, Qiufen Yang, Bryant H Patel, Vinod F Zhong, Wenge |
| description | A series of potent hydroxyethyl amine (HEA) derived inhibitors of β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS β-amyloid (Aβ) in Sprague–Dawley rats following oral administration. |
| doi_str_mv | 10.1021/jm300119p |
| format | Article |
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This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS β-amyloid (Aβ) in Sprague–Dawley rats following oral administration.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm300119p</identifier><identifier>PMID: 22468639</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Oral ; Amyloid beta-Peptides - metabolism ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Animals ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Biological Availability ; Brain - drug effects ; Brain - metabolism ; Crystallography, X-Ray ; Dioxolanes - chemical synthesis ; Dioxolanes - pharmacokinetics ; Dioxolanes - pharmacology ; Dogs ; Drug Design ; Ethylamines - chemical synthesis ; Ethylamines - pharmacokinetics ; Ethylamines - pharmacology ; Humans ; Macaca mulatta ; Male ; Microsomes, Liver - metabolism ; Models, Molecular ; Peptide Fragments - metabolism ; Protein Conformation ; Protein Transport ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2012-11, Vol.55 (21), p.9009-9024</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-a644f8c7a7607e915e000e2201f8c44497af55a1111592a745a8d75d88215fa93</citedby><cites>FETCH-LOGICAL-a315t-a644f8c7a7607e915e000e2201f8c44497af55a1111592a745a8d75d88215fa93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm300119p$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm300119p$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22468639$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weiss, Matthew M</creatorcontrib><creatorcontrib>Williamson, Toni</creatorcontrib><creatorcontrib>Babu-Khan, Safura</creatorcontrib><creatorcontrib>Bartberger, Michael D</creatorcontrib><creatorcontrib>Brown, James</creatorcontrib><creatorcontrib>Chen, Kui</creatorcontrib><creatorcontrib>Cheng, Yuan</creatorcontrib><creatorcontrib>Citron, Martin</creatorcontrib><creatorcontrib>Croghan, Michael D</creatorcontrib><creatorcontrib>Dineen, Thomas A</creatorcontrib><creatorcontrib>Esmay, Joel</creatorcontrib><creatorcontrib>Graceffa, Russell F</creatorcontrib><creatorcontrib>Harried, Scott S</creatorcontrib><creatorcontrib>Hickman, Dean</creatorcontrib><creatorcontrib>Hitchcock, Stephen A</creatorcontrib><creatorcontrib>Horne, Daniel B</creatorcontrib><creatorcontrib>Huang, Hongbing</creatorcontrib><creatorcontrib>Imbeah-Ampiah, Ronke</creatorcontrib><creatorcontrib>Judd, Ted</creatorcontrib><creatorcontrib>Kaller, Matthew R</creatorcontrib><creatorcontrib>Kreiman, Charles R</creatorcontrib><creatorcontrib>La, Daniel S</creatorcontrib><creatorcontrib>Li, Vivian</creatorcontrib><creatorcontrib>Lopez, Patricia</creatorcontrib><creatorcontrib>Louie, Steven</creatorcontrib><creatorcontrib>Monenschein, Holger</creatorcontrib><creatorcontrib>Nguyen, Thomas T</creatorcontrib><creatorcontrib>Pennington, Lewis D</creatorcontrib><creatorcontrib>Rattan, Claire</creatorcontrib><creatorcontrib>San Miguel, Tisha</creatorcontrib><creatorcontrib>Sickmier, E.Allen</creatorcontrib><creatorcontrib>Wahl, Robert C</creatorcontrib><creatorcontrib>Wen, Paul H</creatorcontrib><creatorcontrib>Wood, Stephen</creatorcontrib><creatorcontrib>Xue, Qiufen</creatorcontrib><creatorcontrib>Yang, Bryant H</creatorcontrib><creatorcontrib>Patel, Vinod F</creatorcontrib><creatorcontrib>Zhong, Wenge</creatorcontrib><title>Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid</title><title>Journal of medicinal chemistry</title><addtitle>J. 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pharmacokinetics</subject><subject>Ethylamines - pharmacology</subject><subject>Humans</subject><subject>Macaca mulatta</subject><subject>Male</subject><subject>Microsomes, Liver - metabolism</subject><subject>Models, Molecular</subject><subject>Peptide Fragments - metabolism</subject><subject>Protein Conformation</subject><subject>Protein Transport</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1KHEEQgJsQ0XXjIS8Q-hJIDqP9Oz9HWU0UBEXNeaidqXF7menedPdA5lF8DR_EZ7KXXT2lLgXFV19RVYR85eyUM8HP1oNkjPNq84nMuBYsUyVTn8mMMSEykQt5RI5DWDPGJBfykBwJofIyl9WMPF9gME-Wgm3pnccNeIjGWeo6CvTORbSRPqA3GLalq6n17t-EcTX1MBiLdOFsBGONfaKvL9kDNh4jBKTXdmWWJjof6OMKIr3AwdkQkx3pvVuOIdJ7bMfmfdgiDfLQbyXnw9Q7034hBx30AU_2eU7-_Lp8XFxlN7e_rxfnNxlIrmMGuVJd2RRQ5KzAimtMa6IQjKeqUqoqoNMaeApdCSiUhrItdFuWgusOKjknP3bejXd_RwyxHkxosO_BohtDnfo4k1LrPKE_d2jjXQgeu3rjzQB-qjmrt5-oPz6R2G977bgcsP0g30-fgO87AJpQr93obdryP6I3cTySOw</recordid><startdate>20121108</startdate><enddate>20121108</enddate><creator>Weiss, Matthew M</creator><creator>Williamson, Toni</creator><creator>Babu-Khan, Safura</creator><creator>Bartberger, Michael D</creator><creator>Brown, James</creator><creator>Chen, Kui</creator><creator>Cheng, Yuan</creator><creator>Citron, Martin</creator><creator>Croghan, Michael D</creator><creator>Dineen, Thomas A</creator><creator>Esmay, Joel</creator><creator>Graceffa, Russell F</creator><creator>Harried, Scott S</creator><creator>Hickman, Dean</creator><creator>Hitchcock, Stephen A</creator><creator>Horne, Daniel B</creator><creator>Huang, Hongbing</creator><creator>Imbeah-Ampiah, Ronke</creator><creator>Judd, Ted</creator><creator>Kaller, Matthew R</creator><creator>Kreiman, Charles R</creator><creator>La, Daniel S</creator><creator>Li, Vivian</creator><creator>Lopez, Patricia</creator><creator>Louie, Steven</creator><creator>Monenschein, Holger</creator><creator>Nguyen, Thomas T</creator><creator>Pennington, Lewis D</creator><creator>Rattan, Claire</creator><creator>San Miguel, Tisha</creator><creator>Sickmier, E.Allen</creator><creator>Wahl, Robert C</creator><creator>Wen, Paul H</creator><creator>Wood, Stephen</creator><creator>Xue, Qiufen</creator><creator>Yang, Bryant H</creator><creator>Patel, Vinod F</creator><creator>Zhong, Wenge</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20121108</creationdate><title>Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid</title><author>Weiss, Matthew M ; Williamson, Toni ; Babu-Khan, Safura ; Bartberger, Michael D ; Brown, James ; Chen, Kui ; Cheng, Yuan ; Citron, Martin ; Croghan, Michael D ; Dineen, Thomas A ; Esmay, Joel ; Graceffa, Russell F ; Harried, Scott S ; Hickman, Dean ; Hitchcock, Stephen A ; Horne, Daniel B ; Huang, Hongbing ; Imbeah-Ampiah, Ronke ; Judd, Ted ; Kaller, Matthew R ; Kreiman, Charles R ; La, Daniel S ; Li, Vivian ; Lopez, Patricia ; Louie, Steven ; Monenschein, Holger ; Nguyen, Thomas T ; Pennington, Lewis D ; Rattan, Claire ; San Miguel, Tisha ; Sickmier, E.Allen ; Wahl, Robert C ; Wen, Paul H ; Wood, Stephen ; Xue, Qiufen ; Yang, Bryant H ; Patel, Vinod F ; Zhong, Wenge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-a644f8c7a7607e915e000e2201f8c44497af55a1111592a745a8d75d88215fa93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Administration, Oral</topic><topic>Amyloid beta-Peptides - 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| ispartof | Journal of medicinal chemistry, 2012-11, Vol.55 (21), p.9009-9024 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Administration, Oral Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Aspartic Acid Endopeptidases - antagonists & inhibitors ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Biological Availability Brain - drug effects Brain - metabolism Crystallography, X-Ray Dioxolanes - chemical synthesis Dioxolanes - pharmacokinetics Dioxolanes - pharmacology Dogs Drug Design Ethylamines - chemical synthesis Ethylamines - pharmacokinetics Ethylamines - pharmacology Humans Macaca mulatta Male Microsomes, Liver - metabolism Models, Molecular Peptide Fragments - metabolism Protein Conformation Protein Transport Rats Rats, Sprague-Dawley Stereoisomerism Structure-Activity Relationship |
| title | Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid |
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