Substituted 7‑Amino-5-thio-thiazolo[4,5‑d]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX3CR1)
We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXC...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-04, Vol.56 (8), p.3177-3190 |
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| container_title | Journal of medicinal chemistry |
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| creator | Karlström, Sofia Nordvall, Gunnar Sohn, Daniel Hettman, Andreas Turek, Dominika Åhlin, Kristofer Kers, Annika Claesson, Martina Slivo, Can Lo-Alfredsson, Yvonne Petersson, Carl Bessidskaia, Galina Svensson, Per H Rein, Tobias Jerning, Eva Malmberg, Åsa Ahlgen, Charlotte Ray, Colin Vares, Lauri Ivanov, Vladimir Johansson, Rolf |
| description | We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure–activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists. |
| doi_str_mv | 10.1021/jm3012273 |
| format | Article |
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By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure–activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm3012273</identifier><identifier>PMID: 23516963</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amino Alcohols - chemical synthesis ; Amino Alcohols - pharmacokinetics ; Amino Alcohols - pharmacology ; Animals ; Caco-2 Cells ; CX3C Chemokine Receptor 1 ; Humans ; Multiple Sclerosis - drug therapy ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacokinetics ; Pyrimidines - pharmacology ; Rats ; Receptors, Chemokine - antagonists & inhibitors ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - chemistry ; Thiazoles - pharmacokinetics ; Thiazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2013-04, Vol.56 (8), p.3177-3190</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a296t-6058b3b5621344b80ff88eccb4503123835caafd40b7f029419123e2d865c7103</citedby><cites>FETCH-LOGICAL-a296t-6058b3b5621344b80ff88eccb4503123835caafd40b7f029419123e2d865c7103</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm3012273$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm3012273$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23516963$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Karlström, Sofia</creatorcontrib><creatorcontrib>Nordvall, Gunnar</creatorcontrib><creatorcontrib>Sohn, Daniel</creatorcontrib><creatorcontrib>Hettman, Andreas</creatorcontrib><creatorcontrib>Turek, Dominika</creatorcontrib><creatorcontrib>Åhlin, Kristofer</creatorcontrib><creatorcontrib>Kers, Annika</creatorcontrib><creatorcontrib>Claesson, Martina</creatorcontrib><creatorcontrib>Slivo, Can</creatorcontrib><creatorcontrib>Lo-Alfredsson, Yvonne</creatorcontrib><creatorcontrib>Petersson, Carl</creatorcontrib><creatorcontrib>Bessidskaia, Galina</creatorcontrib><creatorcontrib>Svensson, Per H</creatorcontrib><creatorcontrib>Rein, Tobias</creatorcontrib><creatorcontrib>Jerning, Eva</creatorcontrib><creatorcontrib>Malmberg, Åsa</creatorcontrib><creatorcontrib>Ahlgen, Charlotte</creatorcontrib><creatorcontrib>Ray, Colin</creatorcontrib><creatorcontrib>Vares, Lauri</creatorcontrib><creatorcontrib>Ivanov, Vladimir</creatorcontrib><creatorcontrib>Johansson, Rolf</creatorcontrib><title>Substituted 7‑Amino-5-thio-thiazolo[4,5‑d]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX3CR1)</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure–activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.</description><subject>Amino Alcohols - chemical synthesis</subject><subject>Amino Alcohols - pharmacokinetics</subject><subject>Amino Alcohols - pharmacology</subject><subject>Animals</subject><subject>Caco-2 Cells</subject><subject>CX3C Chemokine Receptor 1</subject><subject>Humans</subject><subject>Multiple Sclerosis - drug therapy</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats</subject><subject>Receptors, Chemokine - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacokinetics</subject><subject>Thiazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtKxDAUhoMoznhZ-AKSjaBgNZeml-UweIMBZVQQREqanjoZ22ZsUkFX4hv4ij6JGUdn5SYHcr7zwf8jtEPJESWMHk9rTihjMV9BfSoYCcKEhKuoTwhjAYsY76ENa6eEEE4ZX0c9xgWN0oj30cd1l1unXeegwPHX--eg1o0JROAm2swf-WYqcx8eCr8rHmavra51oRuwWFp8ZRw0DsumwNdQgXL6BfCgcfLRNNo6i02J3QTwaSuVk9WTv8NjUDBzpsX7wzs-HNODLbRWysrC9u_cRLenJzfD82B0eXYxHIwCydLIBRERSc5zETHKwzBPSFkmCSiVh-InVsKFkrIsQpLHJWFpSFP_C6xIIqFiSvgm2l94Z6157sC6rNZWQVXJBkxnM6-NRJwmcezRgwWqWmNtC2U287ll-5pRks0rz5aVe3b3V9vlNRRL8q9jD-wtAKlsNjVd2_iU_4i-AZAPiAg</recordid><startdate>20130425</startdate><enddate>20130425</enddate><creator>Karlström, Sofia</creator><creator>Nordvall, Gunnar</creator><creator>Sohn, Daniel</creator><creator>Hettman, Andreas</creator><creator>Turek, Dominika</creator><creator>Åhlin, Kristofer</creator><creator>Kers, Annika</creator><creator>Claesson, Martina</creator><creator>Slivo, Can</creator><creator>Lo-Alfredsson, Yvonne</creator><creator>Petersson, Carl</creator><creator>Bessidskaia, Galina</creator><creator>Svensson, Per H</creator><creator>Rein, Tobias</creator><creator>Jerning, Eva</creator><creator>Malmberg, Åsa</creator><creator>Ahlgen, Charlotte</creator><creator>Ray, Colin</creator><creator>Vares, Lauri</creator><creator>Ivanov, Vladimir</creator><creator>Johansson, Rolf</creator><general>American Chemical Society</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>20130425</creationdate><title>Substituted 7‑Amino-5-thio-thiazolo[4,5‑d]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX3CR1)</title><author>Karlström, Sofia ; Nordvall, Gunnar ; Sohn, Daniel ; Hettman, Andreas ; Turek, Dominika ; Åhlin, Kristofer ; Kers, Annika ; Claesson, Martina ; Slivo, Can ; Lo-Alfredsson, Yvonne ; Petersson, Carl ; Bessidskaia, Galina ; Svensson, Per H ; Rein, Tobias ; Jerning, Eva ; Malmberg, Åsa ; Ahlgen, Charlotte ; Ray, Colin ; Vares, Lauri ; Ivanov, Vladimir ; Johansson, Rolf</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a296t-6058b3b5621344b80ff88eccb4503123835caafd40b7f029419123e2d865c7103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Alcohols - chemical synthesis</topic><topic>Amino Alcohols - pharmacokinetics</topic><topic>Amino Alcohols - pharmacology</topic><topic>Animals</topic><topic>Caco-2 Cells</topic><topic>CX3C Chemokine Receptor 1</topic><topic>Humans</topic><topic>Multiple Sclerosis - drug therapy</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Pyrimidines - pharmacology</topic><topic>Rats</topic><topic>Receptors, Chemokine - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - pharmacokinetics</topic><topic>Thiazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Karlström, Sofia</creatorcontrib><creatorcontrib>Nordvall, Gunnar</creatorcontrib><creatorcontrib>Sohn, Daniel</creatorcontrib><creatorcontrib>Hettman, Andreas</creatorcontrib><creatorcontrib>Turek, Dominika</creatorcontrib><creatorcontrib>Åhlin, Kristofer</creatorcontrib><creatorcontrib>Kers, Annika</creatorcontrib><creatorcontrib>Claesson, Martina</creatorcontrib><creatorcontrib>Slivo, Can</creatorcontrib><creatorcontrib>Lo-Alfredsson, Yvonne</creatorcontrib><creatorcontrib>Petersson, Carl</creatorcontrib><creatorcontrib>Bessidskaia, Galina</creatorcontrib><creatorcontrib>Svensson, Per H</creatorcontrib><creatorcontrib>Rein, Tobias</creatorcontrib><creatorcontrib>Jerning, Eva</creatorcontrib><creatorcontrib>Malmberg, Åsa</creatorcontrib><creatorcontrib>Ahlgen, Charlotte</creatorcontrib><creatorcontrib>Ray, Colin</creatorcontrib><creatorcontrib>Vares, Lauri</creatorcontrib><creatorcontrib>Ivanov, Vladimir</creatorcontrib><creatorcontrib>Johansson, Rolf</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Karlström, Sofia</au><au>Nordvall, Gunnar</au><au>Sohn, Daniel</au><au>Hettman, Andreas</au><au>Turek, Dominika</au><au>Åhlin, Kristofer</au><au>Kers, Annika</au><au>Claesson, Martina</au><au>Slivo, Can</au><au>Lo-Alfredsson, Yvonne</au><au>Petersson, Carl</au><au>Bessidskaia, Galina</au><au>Svensson, Per H</au><au>Rein, Tobias</au><au>Jerning, Eva</au><au>Malmberg, Åsa</au><au>Ahlgen, Charlotte</au><au>Ray, Colin</au><au>Vares, Lauri</au><au>Ivanov, Vladimir</au><au>Johansson, Rolf</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Substituted 7‑Amino-5-thio-thiazolo[4,5‑d]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX3CR1)</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-04-25</date><risdate>2013</risdate><volume>56</volume><issue>8</issue><spage>3177</spage><epage>3190</epage><pages>3177-3190</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure–activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23516963</pmid><doi>10.1021/jm3012273</doi><tpages>14</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2013-04, Vol.56 (8), p.3177-3190 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Amino Alcohols - chemical synthesis Amino Alcohols - pharmacokinetics Amino Alcohols - pharmacology Animals Caco-2 Cells CX3C Chemokine Receptor 1 Humans Multiple Sclerosis - drug therapy Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Rats Receptors, Chemokine - antagonists & inhibitors Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacokinetics Thiazoles - pharmacology |
| title | Substituted 7‑Amino-5-thio-thiazolo[4,5‑d]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX3CR1) |
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