Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position
Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inh...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (14), p.4640-4644 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Hamada, Yoshio Nakanishi, Tomoya Suzuki, Kenji Yamaguchi, Ryoji Hamada, Takashi Hidaka, Koushi Ishiura, Shoichi Kiso, Yoshiaki |
| description | Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of these inhibitors, we found that the σ–π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position are described along with the results of the related structure–activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability. |
| doi_str_mv | 10.1016/j.bmcl.2012.05.089 |
| format | Article |
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These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of these inhibitors, we found that the σ–π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position are described along with the results of the related structure–activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.05.089</identifier><identifier>PMID: 22726930</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Alzheimer’s disease ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; BACE1 ; BACE1 inhibitor ; bioavailability ; Biological and medical sciences ; enzyme activity ; Medical sciences ; membrane permeability ; Models, Molecular ; Molecular Structure ; Nitro Compounds - chemistry ; Nitro Compounds - pharmacology ; Peptide Hydrolases - chemical synthesis ; Peptide Hydrolases - pharmacology ; Pharmacology. Drug treatments ; Phthalic Acids - chemistry ; Phthalic Acids - pharmacology ; Structure-Activity Relationship ; structure-activity relationships ; β-Secretase</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-07, Vol.22 (14), p.4640-4644</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-466bd160ad66216543792cf61aef3c27a1bd02495f79e67eb634d534db05f1593</citedby><cites>FETCH-LOGICAL-c391t-466bd160ad66216543792cf61aef3c27a1bd02495f79e67eb634d534db05f1593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2012.05.089$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26151466$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22726930$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamada, Yoshio</creatorcontrib><creatorcontrib>Nakanishi, Tomoya</creatorcontrib><creatorcontrib>Suzuki, Kenji</creatorcontrib><creatorcontrib>Yamaguchi, Ryoji</creatorcontrib><creatorcontrib>Hamada, Takashi</creatorcontrib><creatorcontrib>Hidaka, Koushi</creatorcontrib><creatorcontrib>Ishiura, Shoichi</creatorcontrib><creatorcontrib>Kiso, Yoshiaki</creatorcontrib><title>Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of these inhibitors, we found that the σ–π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position are described along with the results of the related structure–activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.</description><subject>Alzheimer’s disease</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>BACE1</subject><subject>BACE1 inhibitor</subject><subject>bioavailability</subject><subject>Biological and medical sciences</subject><subject>enzyme activity</subject><subject>Medical sciences</subject><subject>membrane permeability</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Nitro Compounds - chemistry</subject><subject>Nitro Compounds - pharmacology</subject><subject>Peptide Hydrolases - chemical synthesis</subject><subject>Peptide Hydrolases - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phthalic Acids - chemistry</subject><subject>Phthalic Acids - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><subject>β-Secretase</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1vEzEQhi0EatPSP8ABfEHqZbfjz40lLiXqB1IFCKjEzfJ67cbRZp3aTqX--zpKgBsHay7PO-N5BqF3BFoCRF6s2n5tx5YCoS2IFubqFZoRLnnDOIjXaAZKQjNX_PcxOsl5BUA4cH6EjintqFQMZujH1_jkRvz5cnFFcJiWoQ8lpow3MWeXc5gesMGimUJJMeS4WZalGYPF2Rrv4zhgU3BZOvyd7iKhhDi9RW-8GbM7O9RTdH999Wtx29x9u_myuLxrLFOkNFzKfiASzCAlJVJw1ilqvSTGeWZpZ0g_AOVK-E452bleMj6I-noQngjFTtH5vu8mxcety0WvQ7ZuHM3k4jZrApRR1TFBK0r3qE11r-S83qSwNum5QnrnUq_0zqXeudQgdHVZQ-8P_bf92g1_I3_kVeDjATBVx-iTmWzI_zhJRL2GrNyHPedN1OYhVeb-Z50k6kEYzOW8Ep_2hKu-noJLOtvgJuuGkJwteojhfz99ATArmcw</recordid><startdate>20120715</startdate><enddate>20120715</enddate><creator>Hamada, Yoshio</creator><creator>Nakanishi, Tomoya</creator><creator>Suzuki, Kenji</creator><creator>Yamaguchi, Ryoji</creator><creator>Hamada, Takashi</creator><creator>Hidaka, Koushi</creator><creator>Ishiura, Shoichi</creator><creator>Kiso, Yoshiaki</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><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></search><sort><creationdate>20120715</creationdate><title>Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position</title><author>Hamada, Yoshio ; Nakanishi, Tomoya ; Suzuki, Kenji ; Yamaguchi, Ryoji ; Hamada, Takashi ; Hidaka, Koushi ; Ishiura, Shoichi ; Kiso, Yoshiaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-466bd160ad66216543792cf61aef3c27a1bd02495f79e67eb634d534db05f1593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alzheimer’s disease</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>BACE1</topic><topic>BACE1 inhibitor</topic><topic>bioavailability</topic><topic>Biological and medical sciences</topic><topic>enzyme activity</topic><topic>Medical sciences</topic><topic>membrane permeability</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Nitro Compounds - chemistry</topic><topic>Nitro Compounds - pharmacology</topic><topic>Peptide Hydrolases - chemical synthesis</topic><topic>Peptide Hydrolases - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Phthalic Acids - chemistry</topic><topic>Phthalic Acids - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><topic>β-Secretase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hamada, Yoshio</creatorcontrib><creatorcontrib>Nakanishi, Tomoya</creatorcontrib><creatorcontrib>Suzuki, Kenji</creatorcontrib><creatorcontrib>Yamaguchi, Ryoji</creatorcontrib><creatorcontrib>Hamada, Takashi</creatorcontrib><creatorcontrib>Hidaka, Koushi</creatorcontrib><creatorcontrib>Ishiura, Shoichi</creatorcontrib><creatorcontrib>Kiso, Yoshiaki</creatorcontrib><collection>AGRIS</collection><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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hamada, Yoshio</au><au>Nakanishi, Tomoya</au><au>Suzuki, Kenji</au><au>Yamaguchi, Ryoji</au><au>Hamada, Takashi</au><au>Hidaka, Koushi</au><au>Ishiura, Shoichi</au><au>Kiso, Yoshiaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-07-15</date><risdate>2012</risdate><volume>22</volume><issue>14</issue><spage>4640</spage><epage>4644</epage><pages>4640-4644</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of these inhibitors, we found that the σ–π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position are described along with the results of the related structure–activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22726930</pmid><doi>10.1016/j.bmcl.2012.05.089</doi><tpages>5</tpages></addata></record> |
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| subjects | Alzheimer’s disease Amyloid Precursor Protein Secretases - antagonists & inhibitors Aspartic Acid Endopeptidases - antagonists & inhibitors BACE1 BACE1 inhibitor bioavailability Biological and medical sciences enzyme activity Medical sciences membrane permeability Models, Molecular Molecular Structure Nitro Compounds - chemistry Nitro Compounds - pharmacology Peptide Hydrolases - chemical synthesis Peptide Hydrolases - pharmacology Pharmacology. Drug treatments Phthalic Acids - chemistry Phthalic Acids - pharmacology Structure-Activity Relationship structure-activity relationships β-Secretase |
| title | Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position |
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