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Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads
Structural biology allowed the identification of 7 as a potent BACE inhibitor (IC 50 = 5 nM). We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer’s disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin c...
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| Published in: | Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (10), p.3158-3160 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| container_end_page | 3160 |
| container_issue | 10 |
| container_start_page | 3158 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 20 |
| creator | Huang, Yifang Strobel, Eric D. Ho, Chih Y. Reynolds, Charles H. Conway, Kelly A. Piesvaux, Jennifer A. Brenneman, Douglas E. Yohrling, George J. Moore Arnold, H. Rosenthal, Daniel Alexander, Richard S. Tounge, Brett A. Mercken, Marc Vandermeeren, Marc Parker, Michael H. Reitz, Allen B. Baxter, Ellen W. |
| description | Structural biology allowed the identification of
7 as a potent BACE inhibitor (IC
50
=
5
nM).
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer’s disease. An X-ray structure of screening hit
1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100× more potent than
1, such as
7 (5
nM
K
i). |
| doi_str_mv | 10.1016/j.bmcl.2010.03.097 |
| format | article |
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7 as a potent BACE inhibitor (IC
50
=
5
nM).
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer’s disease. An X-ray structure of screening hit
1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100× more potent than
1, such as
7 (5
nM
K
i).</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.03.097</identifier><identifier>PMID: 20399652</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Alzheimer’s disease ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Amyloid Precursor Protein Secretases - metabolism ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; Aspartic Acid Endopeptidases - metabolism ; BACE ; BACE inhibitors ; Binding Sites ; Biological and medical sciences ; Computer Simulation ; Humans ; Macrocyclic Compounds - chemical synthesis ; Macrocyclic Compounds - chemistry ; Macrocyclic Compounds - pharmacology ; Medical sciences ; Neuropharmacology ; Pharmacology. Drug treatments ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Quinazolines - chemical synthesis ; Quinazolines - chemistry ; Quinazolines - pharmacology ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-05, Vol.20 (10), p.3158-3160</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-c74abaf31605c330e96076a58add06d178b3a237c210240e5a825096ab46607b3</citedby><cites>FETCH-LOGICAL-c483t-c74abaf31605c330e96076a58add06d178b3a237c210240e5a825096ab46607b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22896327$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20399652$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Yifang</creatorcontrib><creatorcontrib>Strobel, Eric D.</creatorcontrib><creatorcontrib>Ho, Chih Y.</creatorcontrib><creatorcontrib>Reynolds, Charles H.</creatorcontrib><creatorcontrib>Conway, Kelly A.</creatorcontrib><creatorcontrib>Piesvaux, Jennifer A.</creatorcontrib><creatorcontrib>Brenneman, Douglas E.</creatorcontrib><creatorcontrib>Yohrling, George J.</creatorcontrib><creatorcontrib>Moore Arnold, H.</creatorcontrib><creatorcontrib>Rosenthal, Daniel</creatorcontrib><creatorcontrib>Alexander, Richard S.</creatorcontrib><creatorcontrib>Tounge, Brett A.</creatorcontrib><creatorcontrib>Mercken, Marc</creatorcontrib><creatorcontrib>Vandermeeren, Marc</creatorcontrib><creatorcontrib>Parker, Michael H.</creatorcontrib><creatorcontrib>Reitz, Allen B.</creatorcontrib><creatorcontrib>Baxter, Ellen W.</creatorcontrib><title>Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Structural biology allowed the identification of
7 as a potent BACE inhibitor (IC
50
=
5
nM).
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer’s disease. An X-ray structure of screening hit
1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100× more potent than
1, such as
7 (5
nM
K
i).</description><subject>Alzheimer’s disease</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Amyloid Precursor Protein Secretases - metabolism</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>Aspartic Acid Endopeptidases - metabolism</subject><subject>BACE</subject><subject>BACE inhibitors</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Computer Simulation</subject><subject>Humans</subject><subject>Macrocyclic Compounds - chemical synthesis</subject><subject>Macrocyclic Compounds - chemistry</subject><subject>Macrocyclic Compounds - pharmacology</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</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>Quinazolines - chemical synthesis</subject><subject>Quinazolines - chemistry</subject><subject>Quinazolines - pharmacology</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><recordid>eNqFkE1P3DAQhq0KVLbQP9BD5QvqKcv4I06MuCwrKEggOLRSb9bEcYRXSby1s5Xor69Xu9AbnEYaPfNq3oeQLwzmDJg6W82bwfZzDnkBYg66-kBmTCpZCAnlAZmBVlDUWv46Ip9SWgEwCVJ-JEcchNaq5DPyeI82Bvtse2_p5WJ5Rf345Bs_hZjO6cN68oP_i5MPIw0dRTr4jA-hx0if_ESnQEcc94veYZtOyGGHfXKf9_OY_Ly--rG8Ke4evt8uF3eFlbWYCltJbLATTEFphQCXX60UljW2LaiWVXUjkIvKcgZcgiux5mXug41UmWzEMfm2y13H8Hvj0mQGn6zrexxd2CRTyVKL3BPeJ4XQkmvGMsl3ZO6YUnSdWUc_YHw2DMxWuVmZrXKzVW5AmKw8H33dx2-awbWvJy-OM3C6BzBZ7LuIo_XpP8drrQTfBl3sOJe1_fEummS9G61rfXR2Mm3wb_3xD27JnX4</recordid><startdate>20100515</startdate><enddate>20100515</enddate><creator>Huang, Yifang</creator><creator>Strobel, Eric D.</creator><creator>Ho, Chih Y.</creator><creator>Reynolds, Charles H.</creator><creator>Conway, Kelly A.</creator><creator>Piesvaux, Jennifer A.</creator><creator>Brenneman, Douglas E.</creator><creator>Yohrling, George J.</creator><creator>Moore Arnold, H.</creator><creator>Rosenthal, Daniel</creator><creator>Alexander, Richard S.</creator><creator>Tounge, Brett A.</creator><creator>Mercken, Marc</creator><creator>Vandermeeren, Marc</creator><creator>Parker, Michael H.</creator><creator>Reitz, Allen B.</creator><creator>Baxter, Ellen W.</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>20100515</creationdate><title>Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads</title><author>Huang, Yifang ; Strobel, Eric D. ; Ho, Chih Y. ; Reynolds, Charles H. ; Conway, Kelly A. ; Piesvaux, Jennifer A. ; Brenneman, Douglas E. ; Yohrling, George J. ; Moore Arnold, H. ; Rosenthal, Daniel ; Alexander, Richard S. ; Tounge, Brett A. ; Mercken, Marc ; Vandermeeren, Marc ; Parker, Michael H. ; Reitz, Allen B. ; Baxter, Ellen W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-c74abaf31605c330e96076a58add06d178b3a237c210240e5a825096ab46607b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Alzheimer’s disease</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Amyloid Precursor Protein Secretases - metabolism</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>Aspartic Acid Endopeptidases - metabolism</topic><topic>BACE</topic><topic>BACE inhibitors</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Computer Simulation</topic><topic>Humans</topic><topic>Macrocyclic Compounds - chemical synthesis</topic><topic>Macrocyclic Compounds - chemistry</topic><topic>Macrocyclic Compounds - pharmacology</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</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. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Quinazolines - chemical synthesis</topic><topic>Quinazolines - chemistry</topic><topic>Quinazolines - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Yifang</creatorcontrib><creatorcontrib>Strobel, Eric D.</creatorcontrib><creatorcontrib>Ho, Chih Y.</creatorcontrib><creatorcontrib>Reynolds, Charles H.</creatorcontrib><creatorcontrib>Conway, Kelly A.</creatorcontrib><creatorcontrib>Piesvaux, Jennifer A.</creatorcontrib><creatorcontrib>Brenneman, Douglas E.</creatorcontrib><creatorcontrib>Yohrling, George J.</creatorcontrib><creatorcontrib>Moore Arnold, H.</creatorcontrib><creatorcontrib>Rosenthal, Daniel</creatorcontrib><creatorcontrib>Alexander, Richard S.</creatorcontrib><creatorcontrib>Tounge, Brett A.</creatorcontrib><creatorcontrib>Mercken, Marc</creatorcontrib><creatorcontrib>Vandermeeren, Marc</creatorcontrib><creatorcontrib>Parker, Michael H.</creatorcontrib><creatorcontrib>Reitz, Allen B.</creatorcontrib><creatorcontrib>Baxter, Ellen W.</creatorcontrib><collection>Pascal-Francis</collection><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>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>Huang, Yifang</au><au>Strobel, Eric D.</au><au>Ho, Chih Y.</au><au>Reynolds, Charles H.</au><au>Conway, Kelly A.</au><au>Piesvaux, Jennifer A.</au><au>Brenneman, Douglas E.</au><au>Yohrling, George J.</au><au>Moore Arnold, H.</au><au>Rosenthal, Daniel</au><au>Alexander, Richard S.</au><au>Tounge, Brett A.</au><au>Mercken, Marc</au><au>Vandermeeren, Marc</au><au>Parker, Michael H.</au><au>Reitz, Allen B.</au><au>Baxter, Ellen W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-05-15</date><risdate>2010</risdate><volume>20</volume><issue>10</issue><spage>3158</spage><epage>3160</epage><pages>3158-3160</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Structural biology allowed the identification of
7 as a potent BACE inhibitor (IC
50
=
5
nM).
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer’s disease. An X-ray structure of screening hit
1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100× more potent than
1, such as
7 (5
nM
K
i).</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20399652</pmid><doi>10.1016/j.bmcl.2010.03.097</doi><tpages>3</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-05, Vol.20 (10), p.3158-3160 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | ScienceDirect Freedom Collection |
| subjects | Alzheimer’s disease Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Aspartic Acid Endopeptidases - antagonists & inhibitors Aspartic Acid Endopeptidases - metabolism BACE BACE inhibitors Binding Sites Biological and medical sciences Computer Simulation Humans Macrocyclic Compounds - chemical synthesis Macrocyclic Compounds - chemistry Macrocyclic Compounds - pharmacology Medical sciences Neuropharmacology Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Quinazolines - chemical synthesis Quinazolines - chemistry Quinazolines - pharmacology Structure-Activity Relationship |
| title | Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads |
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