2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis
A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [125I]-TA...
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| Veröffentlicht in: | European journal of medicinal chemistry 2016-06, Vol.115, p.14-25 |
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| container_title | European journal of medicinal chemistry |
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| creator | Shukla, Lena Ajram, Laura A. Begg, Malcolm Evans, Brian Graves, Rebecca H. Hodgson, Simon T. Lynn, Sean M. Miah, Afjal H. Percy, Jonathan M. Procopiou, Panayiotis A. Richards, Stephen A. Slack, Robert J. |
| description | A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors.
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•20 amide and amine derivatives of spirocyclic pyrimidines were prepared.•pKi = 8.8 for (R)-(18a) in the [125I]-TARC binding assay, and pIC50 = 8.1 in the [35S]-GTPγS assay.•pA2 = 6.7 in human whole blood actin polymerisation assay.•Compounds found to induce CCR4 endocytosis.•They internalise 50–70% of the cell surface receptors. |
| doi_str_mv | 10.1016/j.ejmech.2016.02.058 |
| format | Article |
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[Display omitted]
•20 amide and amine derivatives of spirocyclic pyrimidines were prepared.•pKi = 8.8 for (R)-(18a) in the [125I]-TARC binding assay, and pIC50 = 8.1 in the [35S]-GTPγS assay.•pA2 = 6.7 in human whole blood actin polymerisation assay.•Compounds found to induce CCR4 endocytosis.•They internalise 50–70% of the cell surface receptors.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2016.02.058</identifier><identifier>PMID: 26991939</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>CCR4 antagonist ; Dose-Response Relationship, Drug ; Endocytosis ; Endocytosis - drug effects ; Humans ; Molecular Structure ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Receptor internalisation ; Receptors, CCR4 - antagonists & inhibitors ; Receptors, CCR4 - metabolism ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Spiro Compounds - pharmacology ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2016-06, Vol.115, p.14-25</ispartof><rights>2016 Elsevier Masson SAS</rights><rights>Copyright © 2016 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-97d029bfe04b25069065137cfffbc97af28170dbab5c2e1bb0ae7963d5fa5eab3</citedby><cites>FETCH-LOGICAL-c408t-97d029bfe04b25069065137cfffbc97af28170dbab5c2e1bb0ae7963d5fa5eab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523416301489$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26991939$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shukla, Lena</creatorcontrib><creatorcontrib>Ajram, Laura A.</creatorcontrib><creatorcontrib>Begg, Malcolm</creatorcontrib><creatorcontrib>Evans, Brian</creatorcontrib><creatorcontrib>Graves, Rebecca H.</creatorcontrib><creatorcontrib>Hodgson, Simon T.</creatorcontrib><creatorcontrib>Lynn, Sean M.</creatorcontrib><creatorcontrib>Miah, Afjal H.</creatorcontrib><creatorcontrib>Percy, Jonathan M.</creatorcontrib><creatorcontrib>Procopiou, Panayiotis A.</creatorcontrib><creatorcontrib>Richards, Stephen A.</creatorcontrib><creatorcontrib>Slack, Robert J.</creatorcontrib><title>2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors.
[Display omitted]
•20 amide and amine derivatives of spirocyclic pyrimidines were prepared.•pKi = 8.8 for (R)-(18a) in the [125I]-TARC binding assay, and pIC50 = 8.1 in the [35S]-GTPγS assay.•pA2 = 6.7 in human whole blood actin polymerisation assay.•Compounds found to induce CCR4 endocytosis.•They internalise 50–70% of the cell surface receptors.</description><subject>CCR4 antagonist</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endocytosis</subject><subject>Endocytosis - drug effects</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Receptor internalisation</subject><subject>Receptors, CCR4 - antagonists & inhibitors</subject><subject>Receptors, CCR4 - metabolism</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - chemistry</subject><subject>Spiro Compounds - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2LFDEQhoMo7rj6D0T6qGDaSjrp7lyEZfyEBUH0JBLyUb1m6E7aJCOMv95eZvXoqSh43nqph5CnDFoGrH91aPGwoPvR8m1rgbcgx3tkx4Z-pB2X4j7ZAecdlbwTF-RRKQcAkD3AQ3LBe6WY6tSOrPzlSN8E89uUNeT0TbTyu0dnIh3paX6xnnJYgg-RCmqWELFZU8VYm_3-s2hMrOYmxVBqaZxZjZ2xSVMToj-6EG-ajA7XmnKD0Sd3qqmE8pg8mMxc8MndvCRf3739sv9Arz-9_7i_uqZOwFipGjxwZScEYbmEXkEvWTe4aZqsU4OZ-MgG8NZY6Tgya8HgoPrOy8lINLa7JM_Pd9ecfh6xVL2E4nCeTcR0LJoNI5OiA9FtqDijLqdSMk563b42-aQZ6FvX-qDPrvWtaw1cb6632LO7hqNd0P8L_ZW7Aa_PAG5__gqYdXEBo0MfNjNV-xT-3_AHKrKSoQ</recordid><startdate>20160610</startdate><enddate>20160610</enddate><creator>Shukla, Lena</creator><creator>Ajram, Laura A.</creator><creator>Begg, Malcolm</creator><creator>Evans, Brian</creator><creator>Graves, Rebecca H.</creator><creator>Hodgson, Simon T.</creator><creator>Lynn, Sean M.</creator><creator>Miah, Afjal H.</creator><creator>Percy, Jonathan M.</creator><creator>Procopiou, Panayiotis A.</creator><creator>Richards, Stephen A.</creator><creator>Slack, Robert J.</creator><general>Elsevier Masson SAS</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>20160610</creationdate><title>2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis</title><author>Shukla, Lena ; Ajram, Laura A. ; Begg, Malcolm ; Evans, Brian ; Graves, Rebecca H. ; Hodgson, Simon T. ; Lynn, Sean M. ; Miah, Afjal H. ; Percy, Jonathan M. ; Procopiou, Panayiotis A. ; Richards, Stephen A. ; Slack, Robert J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-97d029bfe04b25069065137cfffbc97af28170dbab5c2e1bb0ae7963d5fa5eab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>CCR4 antagonist</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endocytosis</topic><topic>Endocytosis - drug effects</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Receptor internalisation</topic><topic>Receptors, CCR4 - antagonists & inhibitors</topic><topic>Receptors, CCR4 - metabolism</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - chemistry</topic><topic>Spiro Compounds - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shukla, Lena</creatorcontrib><creatorcontrib>Ajram, Laura A.</creatorcontrib><creatorcontrib>Begg, Malcolm</creatorcontrib><creatorcontrib>Evans, Brian</creatorcontrib><creatorcontrib>Graves, Rebecca H.</creatorcontrib><creatorcontrib>Hodgson, Simon T.</creatorcontrib><creatorcontrib>Lynn, Sean M.</creatorcontrib><creatorcontrib>Miah, Afjal H.</creatorcontrib><creatorcontrib>Percy, Jonathan M.</creatorcontrib><creatorcontrib>Procopiou, Panayiotis A.</creatorcontrib><creatorcontrib>Richards, Stephen A.</creatorcontrib><creatorcontrib>Slack, Robert J.</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>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shukla, Lena</au><au>Ajram, Laura A.</au><au>Begg, Malcolm</au><au>Evans, Brian</au><au>Graves, Rebecca H.</au><au>Hodgson, Simon T.</au><au>Lynn, Sean M.</au><au>Miah, Afjal H.</au><au>Percy, Jonathan M.</au><au>Procopiou, Panayiotis A.</au><au>Richards, Stephen A.</au><au>Slack, Robert J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2016-06-10</date><risdate>2016</risdate><volume>115</volume><spage>14</spage><epage>25</epage><pages>14-25</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors.
[Display omitted]
•20 amide and amine derivatives of spirocyclic pyrimidines were prepared.•pKi = 8.8 for (R)-(18a) in the [125I]-TARC binding assay, and pIC50 = 8.1 in the [35S]-GTPγS assay.•pA2 = 6.7 in human whole blood actin polymerisation assay.•Compounds found to induce CCR4 endocytosis.•They internalise 50–70% of the cell surface receptors.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>26991939</pmid><doi>10.1016/j.ejmech.2016.02.058</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | CCR4 antagonist Dose-Response Relationship, Drug Endocytosis Endocytosis - drug effects Humans Molecular Structure Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Receptor internalisation Receptors, CCR4 - antagonists & inhibitors Receptors, CCR4 - metabolism Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacology Structure-Activity Relationship |
| title | 2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis |
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