Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic
[Display omitted] Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffo...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2015-11, Vol.23 (21), p.7079-7088 |
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| container_issue | 21 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Liu, Peihong Du, Yongli Song, Lianhua Shen, Jingkang Li, Qunyi |
| description | [Display omitted]
Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC50=222nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake. |
| doi_str_mv | 10.1016/j.bmc.2015.09.024 |
| format | Article |
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Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC50=222nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2015.09.024</identifier><identifier>PMID: 26481657</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Binding Sites ; Biocompatible Materials - chemical synthesis ; Biocompatible Materials - chemistry ; Biocompatible Materials - metabolism ; Cell Line ; CHO Cells ; Cricetinae ; Cricetulus ; Crystallography, X-Ray ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; Glucose - metabolism ; Inhibitor ; Inhibitory Concentration 50 ; Insulin - pharmacology ; Mice ; Molecular Docking Simulation ; Phosphorylation ; Phosphotyrosine - chemistry ; Protein Structure, Tertiary ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism ; PTP1B ; Receptor, Insulin - metabolism ; Structure-Activity Relationship ; Structure–activity relationships ; Type 2 diabetes mellitus</subject><ispartof>Bioorganic & medicinal chemistry, 2015-11, Vol.23 (21), p.7079-7088</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-c419t-b7188d891d1986e55891419de61867eafbb1d7e5cc1d7950136e019a8af1a7723</citedby><cites>FETCH-LOGICAL-c419t-b7188d891d1986e55891419de61867eafbb1d7e5cc1d7950136e019a8af1a7723</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2015.09.024$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26481657$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Peihong</creatorcontrib><creatorcontrib>Du, Yongli</creatorcontrib><creatorcontrib>Song, Lianhua</creatorcontrib><creatorcontrib>Shen, Jingkang</creatorcontrib><creatorcontrib>Li, Qunyi</creatorcontrib><title>Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC50=222nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Biocompatible Materials - chemical synthesis</subject><subject>Biocompatible Materials - chemistry</subject><subject>Biocompatible Materials - metabolism</subject><subject>Cell Line</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Glucose - metabolism</subject><subject>Inhibitor</subject><subject>Inhibitory Concentration 50</subject><subject>Insulin - pharmacology</subject><subject>Mice</subject><subject>Molecular Docking Simulation</subject><subject>Phosphorylation</subject><subject>Phosphotyrosine - chemistry</subject><subject>Protein Structure, Tertiary</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism</subject><subject>PTP1B</subject><subject>Receptor, Insulin - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Structure–activity relationships</subject><subject>Type 2 diabetes mellitus</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi0EokvhAbggH1upCZ5N4tji1K74J1XQQzlbjjPLepXYwXZWyuPwpjjawpGD9Vn2bz7NzEfIW2AlMODvj2U3mnLLoCmZLNm2fkY2UPO6qCoJz8mGSS4KJiS_IK9iPDKWEQkvycWW1wJ4027I72_-hMMNnXxCl25oxAFNsiek2vXU4DDMgw5Un99u73Y0LRPSh8cHuKPWHWxnkw-RGu-Sts66n_RqxHTQDuM87L1bhmI64Cp6tM5fF9pgsiY72p6u5DJQjAkDnQ4-5pOW4KN1SEc7ruRr8mKvh4hvnvSS_Pj08XH3pbj__vnr7va-MDXIVHQtCNELCT1IwbFp8jV_9MhB8Bb1vuugb7ExJotsGFQcGUgt9B50226rS3J19p2C_zXnltRo47qAPIqfo4K24lxA1bYZhTNqcqsx4F5NwY46LAqYWpNRR5WTUWsyikmV155r3j3Zz92I_b-Kv1Fk4MMZwDzkyWJQ0Vh0BnsbciSq9_Y_9n8Awe2hTw</recordid><startdate>20151101</startdate><enddate>20151101</enddate><creator>Liu, Peihong</creator><creator>Du, Yongli</creator><creator>Song, Lianhua</creator><creator>Shen, Jingkang</creator><creator>Li, Qunyi</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></search><sort><creationdate>20151101</creationdate><title>Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic</title><author>Liu, Peihong ; Du, Yongli ; Song, Lianhua ; Shen, Jingkang ; Li, Qunyi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c419t-b7188d891d1986e55891419de61867eafbb1d7e5cc1d7950136e019a8af1a7723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Biocompatible Materials - chemical synthesis</topic><topic>Biocompatible Materials - chemistry</topic><topic>Biocompatible Materials - metabolism</topic><topic>Cell Line</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Glucose - metabolism</topic><topic>Inhibitor</topic><topic>Inhibitory Concentration 50</topic><topic>Insulin - pharmacology</topic><topic>Mice</topic><topic>Molecular Docking Simulation</topic><topic>Phosphorylation</topic><topic>Phosphotyrosine - chemistry</topic><topic>Protein Structure, Tertiary</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism</topic><topic>PTP1B</topic><topic>Receptor, Insulin - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Structure–activity relationships</topic><topic>Type 2 diabetes mellitus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Peihong</creatorcontrib><creatorcontrib>Du, Yongli</creatorcontrib><creatorcontrib>Song, Lianhua</creatorcontrib><creatorcontrib>Shen, Jingkang</creatorcontrib><creatorcontrib>Li, Qunyi</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><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Peihong</au><au>Du, Yongli</au><au>Song, Lianhua</au><au>Shen, Jingkang</au><au>Li, Qunyi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2015-11-01</date><risdate>2015</risdate><volume>23</volume><issue>21</issue><spage>7079</spage><epage>7088</epage><pages>7079-7088</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC50=222nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26481657</pmid><doi>10.1016/j.bmc.2015.09.024</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Binding Sites Biocompatible Materials - chemical synthesis Biocompatible Materials - chemistry Biocompatible Materials - metabolism Cell Line CHO Cells Cricetinae Cricetulus Crystallography, X-Ray Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Glucose - metabolism Inhibitor Inhibitory Concentration 50 Insulin - pharmacology Mice Molecular Docking Simulation Phosphorylation Phosphotyrosine - chemistry Protein Structure, Tertiary Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism PTP1B Receptor, Insulin - metabolism Structure-Activity Relationship Structure–activity relationships Type 2 diabetes mellitus |
| title | Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic |
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