Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease
[Display omitted] The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer’s disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitor...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (4), p.767-774 |
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| creator | Chen, Jian Jeffrey Liu, Qingyian Yuan, Chester Gore, Vijay Lopez, Patricia Ma, Vu Amegadzie, Albert Qian, Wenyuan Judd, Ted C. Minatti, Ana E. Brown, James Cheng, Yuan Xue, May Zhong, Wenge Dineen, Thomas A. Epstein, Oleg Human, Jason Kreiman, Charles Marx, Isaac Weiss, Matthew M. Hitchcock, Stephen A. Powers, Timothy S. Chen, Kui Wen, Paul H. Whittington, Douglas A. Cheng, Alan C. Bartberger, Michael D. Hickman, Dean Werner, Jonathan A. Vargas, Hugo M. Everds, Nancy E. Vonderfecht, Steven L. Dunn, Robert T. Wood, Stephen Fremeau, Robert T. White, Ryan D. Patel, Vinod F. |
| description | [Display omitted]
The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer’s disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model. |
| doi_str_mv | 10.1016/j.bmcl.2014.12.092 |
| format | Article |
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The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer’s disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.12.092</identifier><identifier>PMID: 25613679</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>3-Azaxanthene ; Alzheimer Disease - drug therapy ; Alzheimer’s disease (AD) ; Aminooxazoline ; Amyloid ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Animals ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; Aβ peptides ; Cell Line ; HEK293 Cells ; Humans ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Rats ; Xanthene ; Xanthenes - chemical synthesis ; Xanthenes - chemistry ; Xanthenes - pharmacology ; β-Secretase (BACE1)</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (4), p.767-774</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-7cd361c35216604ff6d5f6d878e3d9171842a2bf9c208801e786b4c10961aa143</citedby><cites>FETCH-LOGICAL-c459t-7cd361c35216604ff6d5f6d878e3d9171842a2bf9c208801e786b4c10961aa143</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X14014000$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25613679$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Jian Jeffrey</creatorcontrib><creatorcontrib>Liu, Qingyian</creatorcontrib><creatorcontrib>Yuan, Chester</creatorcontrib><creatorcontrib>Gore, Vijay</creatorcontrib><creatorcontrib>Lopez, Patricia</creatorcontrib><creatorcontrib>Ma, Vu</creatorcontrib><creatorcontrib>Amegadzie, Albert</creatorcontrib><creatorcontrib>Qian, Wenyuan</creatorcontrib><creatorcontrib>Judd, Ted C.</creatorcontrib><creatorcontrib>Minatti, Ana E.</creatorcontrib><creatorcontrib>Brown, James</creatorcontrib><creatorcontrib>Cheng, Yuan</creatorcontrib><creatorcontrib>Xue, May</creatorcontrib><creatorcontrib>Zhong, Wenge</creatorcontrib><creatorcontrib>Dineen, Thomas A.</creatorcontrib><creatorcontrib>Epstein, Oleg</creatorcontrib><creatorcontrib>Human, Jason</creatorcontrib><creatorcontrib>Kreiman, Charles</creatorcontrib><creatorcontrib>Marx, Isaac</creatorcontrib><creatorcontrib>Weiss, Matthew M.</creatorcontrib><creatorcontrib>Hitchcock, Stephen A.</creatorcontrib><creatorcontrib>Powers, Timothy S.</creatorcontrib><creatorcontrib>Chen, Kui</creatorcontrib><creatorcontrib>Wen, Paul H.</creatorcontrib><creatorcontrib>Whittington, Douglas A.</creatorcontrib><creatorcontrib>Cheng, Alan C.</creatorcontrib><creatorcontrib>Bartberger, Michael D.</creatorcontrib><creatorcontrib>Hickman, Dean</creatorcontrib><creatorcontrib>Werner, Jonathan A.</creatorcontrib><creatorcontrib>Vargas, Hugo M.</creatorcontrib><creatorcontrib>Everds, Nancy E.</creatorcontrib><creatorcontrib>Vonderfecht, Steven L.</creatorcontrib><creatorcontrib>Dunn, Robert T.</creatorcontrib><creatorcontrib>Wood, Stephen</creatorcontrib><creatorcontrib>Fremeau, Robert T.</creatorcontrib><creatorcontrib>White, Ryan D.</creatorcontrib><creatorcontrib>Patel, Vinod F.</creatorcontrib><title>Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer’s disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.</description><subject>3-Azaxanthene</subject><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer’s disease (AD)</subject><subject>Aminooxazoline</subject><subject>Amyloid</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>Aβ peptides</subject><subject>Cell Line</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Rats</subject><subject>Xanthene</subject><subject>Xanthenes - chemical synthesis</subject><subject>Xanthenes - chemistry</subject><subject>Xanthenes - pharmacology</subject><subject>β-Secretase (BACE1)</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkTFuFDEUhi0EIkvgAhTIJc0Mfh6PZ0aiiQIBpEg0INFZHs-z1ivPeLG9UbIVV6DMNTgIh-AkeNmEElFYr_n-78nvJ-Q5sBoYyFebepyNrzkDUQOv2cAfkBUIKapGsPYhWbFBsqofxJcT8iSlDSsgE-IxOeGthEZ2w4p8f4NX6MN2xiXTYCmv9OyWEK71Pni3IG0qvdfXeslrXDBRnWiI2vsbitY6o40Lu0R__qgSmohZJ6RuWbvR5RATtSHSEqTbkIvfaU9zRJ3vl535_RrdjPHXt9tEJ5ew5J-SR1b7hM_u5in5fPH20_n76vLjuw_nZ5eVEe2Qq85MjQTTtBykZMJaObXl9V2PzTRAB73gmo92MJz1PQPsejkKA-UmoDWI5pS8PHq3MXzdYcpqdsmg93rB8if1R8t6JuA_0JYL0UnOCsqPqIkhpYhWbaObdbxRwNShNbVRh9bUoTUFXJXWSujFnX83zjj9jdzXVIDXRwDLQa4cRpWMw8Xg5CKarKbg_uX_Dbd-rDE</recordid><startdate>20150215</startdate><enddate>20150215</enddate><creator>Chen, Jian Jeffrey</creator><creator>Liu, Qingyian</creator><creator>Yuan, Chester</creator><creator>Gore, Vijay</creator><creator>Lopez, Patricia</creator><creator>Ma, Vu</creator><creator>Amegadzie, Albert</creator><creator>Qian, Wenyuan</creator><creator>Judd, Ted C.</creator><creator>Minatti, Ana E.</creator><creator>Brown, James</creator><creator>Cheng, Yuan</creator><creator>Xue, May</creator><creator>Zhong, Wenge</creator><creator>Dineen, Thomas A.</creator><creator>Epstein, Oleg</creator><creator>Human, Jason</creator><creator>Kreiman, Charles</creator><creator>Marx, Isaac</creator><creator>Weiss, Matthew M.</creator><creator>Hitchcock, Stephen A.</creator><creator>Powers, Timothy S.</creator><creator>Chen, Kui</creator><creator>Wen, Paul H.</creator><creator>Whittington, Douglas A.</creator><creator>Cheng, Alan C.</creator><creator>Bartberger, Michael D.</creator><creator>Hickman, Dean</creator><creator>Werner, Jonathan A.</creator><creator>Vargas, Hugo M.</creator><creator>Everds, Nancy E.</creator><creator>Vonderfecht, Steven L.</creator><creator>Dunn, Robert T.</creator><creator>Wood, Stephen</creator><creator>Fremeau, Robert T.</creator><creator>White, Ryan D.</creator><creator>Patel, Vinod F.</creator><general>Elsevier Ltd</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><scope>7QO</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20150215</creationdate><title>Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease</title><author>Chen, Jian Jeffrey ; Liu, Qingyian ; Yuan, Chester ; Gore, Vijay ; Lopez, Patricia ; Ma, Vu ; Amegadzie, Albert ; Qian, Wenyuan ; Judd, Ted C. ; Minatti, Ana E. ; Brown, James ; Cheng, Yuan ; Xue, May ; Zhong, Wenge ; Dineen, Thomas A. ; Epstein, Oleg ; Human, Jason ; Kreiman, Charles ; Marx, Isaac ; Weiss, Matthew M. ; Hitchcock, Stephen A. ; Powers, Timothy S. ; Chen, Kui ; Wen, Paul H. ; Whittington, Douglas A. ; Cheng, Alan C. ; Bartberger, Michael D. ; Hickman, Dean ; Werner, Jonathan A. ; Vargas, Hugo M. ; Everds, Nancy E. ; Vonderfecht, Steven L. ; Dunn, Robert T. ; Wood, Stephen ; Fremeau, Robert T. ; White, Ryan D. ; Patel, Vinod F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-7cd361c35216604ff6d5f6d878e3d9171842a2bf9c208801e786b4c10961aa143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>3-Azaxanthene</topic><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer’s disease (AD)</topic><topic>Aminooxazoline</topic><topic>Amyloid</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>Aβ peptides</topic><topic>Cell Line</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Rats</topic><topic>Xanthene</topic><topic>Xanthenes - chemical synthesis</topic><topic>Xanthenes - chemistry</topic><topic>Xanthenes - pharmacology</topic><topic>β-Secretase (BACE1)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Jian Jeffrey</creatorcontrib><creatorcontrib>Liu, Qingyian</creatorcontrib><creatorcontrib>Yuan, Chester</creatorcontrib><creatorcontrib>Gore, Vijay</creatorcontrib><creatorcontrib>Lopez, Patricia</creatorcontrib><creatorcontrib>Ma, Vu</creatorcontrib><creatorcontrib>Amegadzie, Albert</creatorcontrib><creatorcontrib>Qian, Wenyuan</creatorcontrib><creatorcontrib>Judd, Ted C.</creatorcontrib><creatorcontrib>Minatti, Ana E.</creatorcontrib><creatorcontrib>Brown, James</creatorcontrib><creatorcontrib>Cheng, Yuan</creatorcontrib><creatorcontrib>Xue, May</creatorcontrib><creatorcontrib>Zhong, Wenge</creatorcontrib><creatorcontrib>Dineen, Thomas A.</creatorcontrib><creatorcontrib>Epstein, Oleg</creatorcontrib><creatorcontrib>Human, Jason</creatorcontrib><creatorcontrib>Kreiman, Charles</creatorcontrib><creatorcontrib>Marx, Isaac</creatorcontrib><creatorcontrib>Weiss, Matthew M.</creatorcontrib><creatorcontrib>Hitchcock, Stephen A.</creatorcontrib><creatorcontrib>Powers, Timothy S.</creatorcontrib><creatorcontrib>Chen, Kui</creatorcontrib><creatorcontrib>Wen, Paul H.</creatorcontrib><creatorcontrib>Whittington, Douglas A.</creatorcontrib><creatorcontrib>Cheng, Alan C.</creatorcontrib><creatorcontrib>Bartberger, Michael D.</creatorcontrib><creatorcontrib>Hickman, Dean</creatorcontrib><creatorcontrib>Werner, Jonathan A.</creatorcontrib><creatorcontrib>Vargas, Hugo M.</creatorcontrib><creatorcontrib>Everds, Nancy E.</creatorcontrib><creatorcontrib>Vonderfecht, Steven L.</creatorcontrib><creatorcontrib>Dunn, Robert T.</creatorcontrib><creatorcontrib>Wood, Stephen</creatorcontrib><creatorcontrib>Fremeau, Robert T.</creatorcontrib><creatorcontrib>White, Ryan D.</creatorcontrib><creatorcontrib>Patel, Vinod F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Jian Jeffrey</au><au>Liu, Qingyian</au><au>Yuan, Chester</au><au>Gore, Vijay</au><au>Lopez, Patricia</au><au>Ma, Vu</au><au>Amegadzie, Albert</au><au>Qian, Wenyuan</au><au>Judd, Ted C.</au><au>Minatti, Ana E.</au><au>Brown, James</au><au>Cheng, Yuan</au><au>Xue, May</au><au>Zhong, Wenge</au><au>Dineen, Thomas A.</au><au>Epstein, Oleg</au><au>Human, Jason</au><au>Kreiman, Charles</au><au>Marx, Isaac</au><au>Weiss, Matthew M.</au><au>Hitchcock, Stephen A.</au><au>Powers, Timothy S.</au><au>Chen, Kui</au><au>Wen, Paul H.</au><au>Whittington, Douglas A.</au><au>Cheng, Alan C.</au><au>Bartberger, Michael D.</au><au>Hickman, Dean</au><au>Werner, Jonathan A.</au><au>Vargas, Hugo M.</au><au>Everds, Nancy E.</au><au>Vonderfecht, Steven L.</au><au>Dunn, Robert T.</au><au>Wood, Stephen</au><au>Fremeau, Robert T.</au><au>White, Ryan D.</au><au>Patel, Vinod F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-02-15</date><risdate>2015</risdate><volume>25</volume><issue>4</issue><spage>767</spage><epage>774</epage><pages>767-774</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer’s disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25613679</pmid><doi>10.1016/j.bmcl.2014.12.092</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (4), p.767-774 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 3-Azaxanthene Alzheimer Disease - drug therapy Alzheimer’s disease (AD) Aminooxazoline Amyloid Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Aspartic Acid Endopeptidases - antagonists & inhibitors Aβ peptides Cell Line HEK293 Cells Humans Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Rats Xanthene Xanthenes - chemical synthesis Xanthenes - chemistry Xanthenes - pharmacology β-Secretase (BACE1) |
| title | Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease |
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