Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors
[Display omitted] Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containi...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-04, Vol.26 (8), p.2057-2064 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Fairhurst, Robin A. Marsilje, Thomas H. Stutz, Stefan Boos, Andreas Niklaus, Michel Chen, Bei Jiang, Songchun Lu, Wenshuo Furet, Pascal McCarthy, Clive Stauffer, Frédéric Guagnano, Vito Vaupel, Andrea Michellys, Pierre-Yves Schnell, Christian Jeay, Sébastien |
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Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse. |
| doi_str_mv | 10.1016/j.bmcl.2016.02.075 |
| format | Article |
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Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.02.075</identifier><identifier>PMID: 26951753</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Insulin-like growth factor receptor-1 ; Kinase inhibitor ; Mice ; Mice, Nude ; Molecular Structure ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - pathology ; NIH 3T3 Cells ; Oncology ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Pyrazines - chemical synthesis ; Pyrazines - chemistry ; Pyrazines - pharmacology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Pyrroles - chemical synthesis ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Receptor, IGF Type 1 - antagonists & inhibitors ; Receptor, IGF Type 1 - metabolism ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-04, Vol.26 (8), p.2057-2064</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-458d0279e766485ebb09a1731b031f79092befcf229f2189fb3ab9b618e133d53</citedby><cites>FETCH-LOGICAL-c356t-458d0279e766485ebb09a1731b031f79092befcf229f2189fb3ab9b618e133d53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X16301998$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26951753$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fairhurst, Robin A.</creatorcontrib><creatorcontrib>Marsilje, Thomas H.</creatorcontrib><creatorcontrib>Stutz, Stefan</creatorcontrib><creatorcontrib>Boos, Andreas</creatorcontrib><creatorcontrib>Niklaus, Michel</creatorcontrib><creatorcontrib>Chen, Bei</creatorcontrib><creatorcontrib>Jiang, Songchun</creatorcontrib><creatorcontrib>Lu, Wenshuo</creatorcontrib><creatorcontrib>Furet, Pascal</creatorcontrib><creatorcontrib>McCarthy, Clive</creatorcontrib><creatorcontrib>Stauffer, Frédéric</creatorcontrib><creatorcontrib>Guagnano, Vito</creatorcontrib><creatorcontrib>Vaupel, Andrea</creatorcontrib><creatorcontrib>Michellys, Pierre-Yves</creatorcontrib><creatorcontrib>Schnell, Christian</creatorcontrib><creatorcontrib>Jeay, Sébastien</creatorcontrib><title>Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Insulin-like growth factor receptor-1</subject><subject>Kinase inhibitor</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular Structure</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - pathology</subject><subject>NIH 3T3 Cells</subject><subject>Oncology</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrazines - chemical synthesis</subject><subject>Pyrazines - chemistry</subject><subject>Pyrazines - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Pyrroles - chemical synthesis</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Receptor, IGF Type 1 - antagonists & inhibitors</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtr3DAUhUVIaKZp_0AWwctkIUdvW5BNCHlBIBBaKJQiLPma0WBbjuQJzL-P3Em7zOrcezn3wPkQOqWkpISqy01pB9eXLM8lYSWp5AFaUaEE5oLIQ7QiWhFca_HrGH1NaUMIFUSIL-iYKS1pJfkKvT5Psx98amYfxiJ0RVNI_JvjaQ3jrsfnDLud673DMK8hXuAha77_3f5ggZvBj2HaxRj6RXJU60coEkQPacl7vL_D9KXw49pbP4eYvqGjrukTfP_QE_Tz7vbHzQN-er5_vLl-wo5LNWMh65awSkOllKglWEt0QytOLeG0qzTRzELnOsZ0x2itO8sbq62iNVDOW8lP0Pk-d4rhdQtpNrmmg75vRgjbZGhVKaKFpCJb2d7qYkgpQmem3KSJO0OJWVCbjVlQmwW1Icxk1Pnp7CN_awdo_7_8Y5sNV3sD5JZvHqJJzsPooPUR3Gza4D_LfwcaaY82</recordid><startdate>20160415</startdate><enddate>20160415</enddate><creator>Fairhurst, Robin A.</creator><creator>Marsilje, Thomas H.</creator><creator>Stutz, Stefan</creator><creator>Boos, Andreas</creator><creator>Niklaus, Michel</creator><creator>Chen, Bei</creator><creator>Jiang, Songchun</creator><creator>Lu, Wenshuo</creator><creator>Furet, Pascal</creator><creator>McCarthy, Clive</creator><creator>Stauffer, Frédéric</creator><creator>Guagnano, Vito</creator><creator>Vaupel, Andrea</creator><creator>Michellys, Pierre-Yves</creator><creator>Schnell, Christian</creator><creator>Jeay, Sébastien</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>20160415</creationdate><title>Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors</title><author>Fairhurst, Robin A. ; Marsilje, Thomas H. ; Stutz, Stefan ; Boos, Andreas ; Niklaus, Michel ; Chen, Bei ; Jiang, Songchun ; Lu, Wenshuo ; Furet, Pascal ; McCarthy, Clive ; Stauffer, Frédéric ; Guagnano, Vito ; Vaupel, Andrea ; Michellys, Pierre-Yves ; Schnell, Christian ; Jeay, Sébastien</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-458d0279e766485ebb09a1731b031f79092befcf229f2189fb3ab9b618e133d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Insulin-like growth factor receptor-1</topic><topic>Kinase inhibitor</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Molecular Structure</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - pathology</topic><topic>NIH 3T3 Cells</topic><topic>Oncology</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrazines - chemical synthesis</topic><topic>Pyrazines - chemistry</topic><topic>Pyrazines - pharmacology</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Pyrroles - chemical synthesis</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Receptor, IGF Type 1 - antagonists & inhibitors</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fairhurst, Robin A.</creatorcontrib><creatorcontrib>Marsilje, Thomas H.</creatorcontrib><creatorcontrib>Stutz, Stefan</creatorcontrib><creatorcontrib>Boos, Andreas</creatorcontrib><creatorcontrib>Niklaus, Michel</creatorcontrib><creatorcontrib>Chen, Bei</creatorcontrib><creatorcontrib>Jiang, Songchun</creatorcontrib><creatorcontrib>Lu, Wenshuo</creatorcontrib><creatorcontrib>Furet, Pascal</creatorcontrib><creatorcontrib>McCarthy, Clive</creatorcontrib><creatorcontrib>Stauffer, Frédéric</creatorcontrib><creatorcontrib>Guagnano, Vito</creatorcontrib><creatorcontrib>Vaupel, Andrea</creatorcontrib><creatorcontrib>Michellys, Pierre-Yves</creatorcontrib><creatorcontrib>Schnell, Christian</creatorcontrib><creatorcontrib>Jeay, Sébastien</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 letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fairhurst, Robin A.</au><au>Marsilje, Thomas H.</au><au>Stutz, Stefan</au><au>Boos, Andreas</au><au>Niklaus, Michel</au><au>Chen, Bei</au><au>Jiang, Songchun</au><au>Lu, Wenshuo</au><au>Furet, Pascal</au><au>McCarthy, Clive</au><au>Stauffer, Frédéric</au><au>Guagnano, Vito</au><au>Vaupel, Andrea</au><au>Michellys, Pierre-Yves</au><au>Schnell, Christian</au><au>Jeay, Sébastien</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-04-15</date><risdate>2016</risdate><volume>26</volume><issue>8</issue><spage>2057</spage><epage>2064</epage><pages>2057-2064</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26951753</pmid><doi>10.1016/j.bmcl.2016.02.075</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2016-04, Vol.26 (8), p.2057-2064 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Proliferation - drug effects Dose-Response Relationship, Drug Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Insulin-like growth factor receptor-1 Kinase inhibitor Mice Mice, Nude Molecular Structure Neoplasms, Experimental - drug therapy Neoplasms, Experimental - pathology NIH 3T3 Cells Oncology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Receptor, IGF Type 1 - antagonists & inhibitors Receptor, IGF Type 1 - metabolism Structure-Activity Relationship Xenograft Model Antitumor Assays |
| title | Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors |
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