Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model
In this letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the wild type preclin...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (21), p.6231-6236 |
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| creator | Truong, Anh P. Tóth, Gergley Probst, Gary D. Sealy, Jennifer M. Bowers, Simeon Wone, David W.G. Dressen, Darren Hom, Roy K. Konradi, Andrei W. Sham, Hing L. Wu, Jing Peterson, Brian T. Ruslim, Lany Bova, Michael P. Kholodenko, Dora Motter, Ruth N. Bard, Frédérique Santiago, Pamela Ni, Huifang Chian, David Soriano, Ferdie Cole, Tracy Brigham, Elizabeth F. Wong, Karina Zmolek, Wes Goldbach, Erich Samant, Bhushan Chen, Linda Zhang, Hongbing Nakamura, David F. Quinn, Kevin P. Yednock, Ted A. Sauer, John-Michael |
| description | In this letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing
16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the
wild type preclinical Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days.
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing
16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical
wild type Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days. |
| doi_str_mv | 10.1016/j.bmcl.2010.08.102 |
| format | Article |
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16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the
wild type preclinical Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days.
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing
16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical
wild type Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.08.102</identifier><identifier>PMID: 20833041</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Alkylation ; Alzheimer Disease ; Alzheimer’s disease ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Animals ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; BACE-1 inhibitor ; Biological and medical sciences ; Brain - metabolism ; Cell Line ; Dogs ; Drug Design ; Ethylamines - chemical synthesis ; Ethylamines - pharmacology ; Fluorine ; Guinea Pigs ; Humans ; Hydroxyethylamine (HEA) ; Indicators and Reagents ; Medical sciences ; Neuropharmacology ; Pharmacology. Drug treatments ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - pharmacokinetics ; Protease Inhibitors - pharmacology ; Protein Binding ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-11, Vol.20 (21), p.6231-6236</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-2c7689cff0ba0d3e67a7926ad5cee9b3bd863919f597a92feb4ffd32e457bff23</citedby><cites>FETCH-LOGICAL-c483t-2c7689cff0ba0d3e67a7926ad5cee9b3bd863919f597a92feb4ffd32e457bff23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X10012382$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23419243$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20833041$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Truong, Anh P.</creatorcontrib><creatorcontrib>Tóth, Gergley</creatorcontrib><creatorcontrib>Probst, Gary D.</creatorcontrib><creatorcontrib>Sealy, Jennifer M.</creatorcontrib><creatorcontrib>Bowers, Simeon</creatorcontrib><creatorcontrib>Wone, David W.G.</creatorcontrib><creatorcontrib>Dressen, Darren</creatorcontrib><creatorcontrib>Hom, Roy K.</creatorcontrib><creatorcontrib>Konradi, Andrei W.</creatorcontrib><creatorcontrib>Sham, Hing L.</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Peterson, Brian T.</creatorcontrib><creatorcontrib>Ruslim, Lany</creatorcontrib><creatorcontrib>Bova, Michael P.</creatorcontrib><creatorcontrib>Kholodenko, Dora</creatorcontrib><creatorcontrib>Motter, Ruth N.</creatorcontrib><creatorcontrib>Bard, Frédérique</creatorcontrib><creatorcontrib>Santiago, Pamela</creatorcontrib><creatorcontrib>Ni, Huifang</creatorcontrib><creatorcontrib>Chian, David</creatorcontrib><creatorcontrib>Soriano, Ferdie</creatorcontrib><creatorcontrib>Cole, Tracy</creatorcontrib><creatorcontrib>Brigham, Elizabeth F.</creatorcontrib><creatorcontrib>Wong, Karina</creatorcontrib><creatorcontrib>Zmolek, Wes</creatorcontrib><creatorcontrib>Goldbach, Erich</creatorcontrib><creatorcontrib>Samant, Bhushan</creatorcontrib><creatorcontrib>Chen, Linda</creatorcontrib><creatorcontrib>Zhang, Hongbing</creatorcontrib><creatorcontrib>Nakamura, David F.</creatorcontrib><creatorcontrib>Quinn, Kevin P.</creatorcontrib><creatorcontrib>Yednock, Ted A.</creatorcontrib><creatorcontrib>Sauer, John-Michael</creatorcontrib><title>Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>In this letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing
16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the
wild type preclinical Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days.
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing
16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical
wild type Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days.</description><subject>Alkylation</subject><subject>Alzheimer Disease</subject><subject>Alzheimer’s disease</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>BACE-1 inhibitor</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Cell Line</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Ethylamines - chemical synthesis</subject><subject>Ethylamines - pharmacology</subject><subject>Fluorine</subject><subject>Guinea Pigs</subject><subject>Humans</subject><subject>Hydroxyethylamine (HEA)</subject><subject>Indicators and Reagents</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - pharmacokinetics</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Protein Binding</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU-P0zAQxS0EYsvCF-CAckHAIcX_4tjSXkopuyuttBeQuFmOPaaunKTYKSLfHpcW9gYXj_X0m6eZNwi9JHhJMBHvd8uut3FJcRGwLBp9hBaEC14zjpvHaIGVwLVU_OsFepbzDmPCMedP0QXFkjHMyQL5j5DDt6EafWXKm0yMcwXeB2tsGA-52s4ujT9nmLZzNH0YoHp7s1m9qz6s1puaVGHYhi5MYyq_ylT7BDaGoXTH4hf6UvrRQXyOnngTM7w410v05dPm8_qmvru_vl2v7mrLJZtqalshlfUedwY7BqI1raLCuMYCqI51TgqmiPKNao2iHjruvWMUeNN23lN2id6cfPdp_H6APOk-ZAsxmgHKNlrKsrYgTP2XbJuWC9z8JumJtGnMOYHX-1Q2S7MmWB8PoXf6eAh9PITGsmjHQV6d7Q9dD-5vy5_kC_D6DJhc0vLJDDbkB45xoihnhbs6cVBi-xEg6WwDDBZcKFlP2o3hX3P8Avefpk0</recordid><startdate>20101101</startdate><enddate>20101101</enddate><creator>Truong, Anh P.</creator><creator>Tóth, Gergley</creator><creator>Probst, Gary D.</creator><creator>Sealy, Jennifer M.</creator><creator>Bowers, Simeon</creator><creator>Wone, David W.G.</creator><creator>Dressen, Darren</creator><creator>Hom, Roy K.</creator><creator>Konradi, Andrei W.</creator><creator>Sham, Hing L.</creator><creator>Wu, Jing</creator><creator>Peterson, Brian T.</creator><creator>Ruslim, Lany</creator><creator>Bova, Michael P.</creator><creator>Kholodenko, Dora</creator><creator>Motter, Ruth N.</creator><creator>Bard, Frédérique</creator><creator>Santiago, Pamela</creator><creator>Ni, Huifang</creator><creator>Chian, David</creator><creator>Soriano, Ferdie</creator><creator>Cole, Tracy</creator><creator>Brigham, Elizabeth F.</creator><creator>Wong, Karina</creator><creator>Zmolek, Wes</creator><creator>Goldbach, Erich</creator><creator>Samant, Bhushan</creator><creator>Chen, Linda</creator><creator>Zhang, Hongbing</creator><creator>Nakamura, David F.</creator><creator>Quinn, Kevin P.</creator><creator>Yednock, Ted A.</creator><creator>Sauer, John-Michael</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>IQODW</scope><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>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20101101</creationdate><title>Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model</title><author>Truong, Anh P. ; Tóth, Gergley ; Probst, Gary D. ; Sealy, Jennifer M. ; Bowers, Simeon ; Wone, David W.G. ; Dressen, Darren ; Hom, Roy K. ; Konradi, Andrei W. ; Sham, Hing L. ; Wu, Jing ; Peterson, Brian T. ; Ruslim, Lany ; Bova, Michael P. ; Kholodenko, Dora ; Motter, Ruth N. ; Bard, Frédérique ; Santiago, Pamela ; Ni, Huifang ; Chian, David ; Soriano, Ferdie ; Cole, Tracy ; Brigham, Elizabeth F. ; Wong, Karina ; Zmolek, Wes ; Goldbach, Erich ; Samant, Bhushan ; Chen, Linda ; Zhang, Hongbing ; Nakamura, David F. ; Quinn, Kevin P. ; Yednock, Ted A. ; Sauer, John-Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-2c7689cff0ba0d3e67a7926ad5cee9b3bd863919f597a92feb4ffd32e457bff23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Alkylation</topic><topic>Alzheimer Disease</topic><topic>Alzheimer’s disease</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>BACE-1 inhibitor</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>Cell Line</topic><topic>Dogs</topic><topic>Drug Design</topic><topic>Ethylamines - chemical synthesis</topic><topic>Ethylamines - pharmacology</topic><topic>Fluorine</topic><topic>Guinea Pigs</topic><topic>Humans</topic><topic>Hydroxyethylamine (HEA)</topic><topic>Indicators and Reagents</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - pharmacokinetics</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Protein Binding</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. 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These efforts culminate in producing
16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the
wild type preclinical Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days.
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing
16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical
wild type Hartley guinea pig animal model when dosed orally at 30
mpk BID for 2.5
days.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20833041</pmid><doi>10.1016/j.bmcl.2010.08.102</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-11, Vol.20 (21), p.6231-6236 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_883046139 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Alkylation Alzheimer Disease Alzheimer’s disease Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Aspartic Acid Endopeptidases - antagonists & inhibitors BACE-1 inhibitor Biological and medical sciences Brain - metabolism Cell Line Dogs Drug Design Ethylamines - chemical synthesis Ethylamines - pharmacology Fluorine Guinea Pigs Humans Hydroxyethylamine (HEA) Indicators and Reagents Medical sciences Neuropharmacology Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - pharmacokinetics Protease Inhibitors - pharmacology Protein Binding Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Structure-Activity Relationship |
| title | Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model |
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