Orally Bioavailable Competitive CCR5 Antagonists
The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders...
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| Veröffentlicht in: | Journal of medicinal chemistry 2004-04, Vol.47 (8), p.1939-1955 |
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| container_end_page | 1955 |
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| container_issue | 8 |
| container_start_page | 1939 |
| container_title | Journal of medicinal chemistry |
| container_volume | 47 |
| creator | Thoma, Gebhard Nuninger, François Schaefer, Marc Akyel, Kayhan G Albert, Rainer Beerli, Christian Bruns, Christian Francotte, Eric Luyten, Marcel MacKenzie, Duncan Oberer, Lukas Streiff, Markus B Wagner, Trixie Walter, Hansrudolf Weckbecker, Gisbert Zerwes, Hans-Guenter |
| description | The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure−activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models. |
| doi_str_mv | 10.1021/jm031046g |
| format | Article |
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Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure−activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm031046g</identifier><identifier>PMID: 15055994</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Biological and medical sciences ; Biological Availability ; Calcium - metabolism ; CCR5 Receptor Antagonists ; Cell Line ; Chemotaxis, Leukocyte ; Cricetinae ; Crystallography, X-Ray ; Diphenylamine - analogs & derivatives ; Diphenylamine - chemical synthesis ; Diphenylamine - chemistry ; Diphenylamine - pharmacology ; Humans ; Immunomodulators ; In Vitro Techniques ; Lymphocytes - drug effects ; Lymphocytes - physiology ; Macaca fascicularis ; Medical sciences ; Mice ; Molecular Structure ; Pharmacology. Drug treatments ; Pyrimidinones - chemical synthesis ; Pyrimidinones - chemistry ; Pyrimidinones - pharmacology ; Radioligand Assay ; Rats ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2004-04, Vol.47 (8), p.1939-1955</ispartof><rights>Copyright © 2004 American Chemical Society</rights><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-b8f7241f7fe0e18289ff4e13c9c36ad76623ab143fd4cb06af44eff1dc88e5ac3</citedby><cites>FETCH-LOGICAL-a381t-b8f7241f7fe0e18289ff4e13c9c36ad76623ab143fd4cb06af44eff1dc88e5ac3</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/jm031046g$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm031046g$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15646932$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15055994$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thoma, Gebhard</creatorcontrib><creatorcontrib>Nuninger, François</creatorcontrib><creatorcontrib>Schaefer, Marc</creatorcontrib><creatorcontrib>Akyel, Kayhan G</creatorcontrib><creatorcontrib>Albert, Rainer</creatorcontrib><creatorcontrib>Beerli, Christian</creatorcontrib><creatorcontrib>Bruns, Christian</creatorcontrib><creatorcontrib>Francotte, Eric</creatorcontrib><creatorcontrib>Luyten, Marcel</creatorcontrib><creatorcontrib>MacKenzie, Duncan</creatorcontrib><creatorcontrib>Oberer, Lukas</creatorcontrib><creatorcontrib>Streiff, Markus B</creatorcontrib><creatorcontrib>Wagner, Trixie</creatorcontrib><creatorcontrib>Walter, Hansrudolf</creatorcontrib><creatorcontrib>Weckbecker, Gisbert</creatorcontrib><creatorcontrib>Zerwes, Hans-Guenter</creatorcontrib><title>Orally Bioavailable Competitive CCR5 Antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure−activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Calcium - metabolism</subject><subject>CCR5 Receptor Antagonists</subject><subject>Cell Line</subject><subject>Chemotaxis, Leukocyte</subject><subject>Cricetinae</subject><subject>Crystallography, X-Ray</subject><subject>Diphenylamine - analogs & derivatives</subject><subject>Diphenylamine - chemical synthesis</subject><subject>Diphenylamine - chemistry</subject><subject>Diphenylamine - pharmacology</subject><subject>Humans</subject><subject>Immunomodulators</subject><subject>In Vitro Techniques</subject><subject>Lymphocytes - drug effects</subject><subject>Lymphocytes - physiology</subject><subject>Macaca fascicularis</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrimidinones - chemical synthesis</subject><subject>Pyrimidinones - chemistry</subject><subject>Pyrimidinones - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MtKAzEUBuAgiq2XhS8g3Si4GM1tksyyFq1CsaL1sgtn0qRMnUtNpqJvb6TFunB1DpyPn8OP0BHB5wRTcjGvMCOYi9kW6pKU4oQrzLdRF2NKEyoo66C9EOYYR0bZLuqQFKdplvEuwmMPZfnVuywa-ICihLy0vUFTLWxbtMVH3AcPaa9ftzBr6iK04QDtOCiDPVzPffR0fTUZ3CSj8fB20B8lwBRpk1w5STlx0llsiaIqc45bwkxmmICpFPEryAlnbspNjgU4zq1zZGqUsikYto9OV7kL37wvbWh1VQRjyxJq2yyDlkQqKSSJ8GwFjW9C8NbphS8q8F-aYP1Tj_6tJ9rjdegyr-x0I9d9RHCyBhAMlM5DbYrwxwkuMkajS1YuVmI_f-_g37SQTKZ6cv-oh88qu8teX_T9JhdM0PNm6evY3T8PfgM5KocN</recordid><startdate>20040408</startdate><enddate>20040408</enddate><creator>Thoma, Gebhard</creator><creator>Nuninger, François</creator><creator>Schaefer, Marc</creator><creator>Akyel, Kayhan G</creator><creator>Albert, Rainer</creator><creator>Beerli, Christian</creator><creator>Bruns, Christian</creator><creator>Francotte, Eric</creator><creator>Luyten, Marcel</creator><creator>MacKenzie, Duncan</creator><creator>Oberer, Lukas</creator><creator>Streiff, Markus B</creator><creator>Wagner, Trixie</creator><creator>Walter, Hansrudolf</creator><creator>Weckbecker, Gisbert</creator><creator>Zerwes, Hans-Guenter</creator><general>American Chemical Society</general><scope>BSCLL</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>20040408</creationdate><title>Orally Bioavailable Competitive CCR5 Antagonists</title><author>Thoma, Gebhard ; Nuninger, François ; Schaefer, Marc ; Akyel, Kayhan G ; Albert, Rainer ; Beerli, Christian ; Bruns, Christian ; Francotte, Eric ; Luyten, Marcel ; MacKenzie, Duncan ; Oberer, Lukas ; Streiff, Markus B ; Wagner, Trixie ; Walter, Hansrudolf ; Weckbecker, Gisbert ; Zerwes, Hans-Guenter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-b8f7241f7fe0e18289ff4e13c9c36ad76623ab143fd4cb06af44eff1dc88e5ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Calcium - metabolism</topic><topic>CCR5 Receptor Antagonists</topic><topic>Cell Line</topic><topic>Chemotaxis, Leukocyte</topic><topic>Cricetinae</topic><topic>Crystallography, X-Ray</topic><topic>Diphenylamine - analogs & derivatives</topic><topic>Diphenylamine - chemical synthesis</topic><topic>Diphenylamine - chemistry</topic><topic>Diphenylamine - pharmacology</topic><topic>Humans</topic><topic>Immunomodulators</topic><topic>In Vitro Techniques</topic><topic>Lymphocytes - drug effects</topic><topic>Lymphocytes - physiology</topic><topic>Macaca fascicularis</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrimidinones - chemical synthesis</topic><topic>Pyrimidinones - chemistry</topic><topic>Pyrimidinones - pharmacology</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thoma, Gebhard</creatorcontrib><creatorcontrib>Nuninger, François</creatorcontrib><creatorcontrib>Schaefer, Marc</creatorcontrib><creatorcontrib>Akyel, Kayhan G</creatorcontrib><creatorcontrib>Albert, Rainer</creatorcontrib><creatorcontrib>Beerli, Christian</creatorcontrib><creatorcontrib>Bruns, Christian</creatorcontrib><creatorcontrib>Francotte, Eric</creatorcontrib><creatorcontrib>Luyten, Marcel</creatorcontrib><creatorcontrib>MacKenzie, Duncan</creatorcontrib><creatorcontrib>Oberer, Lukas</creatorcontrib><creatorcontrib>Streiff, Markus B</creatorcontrib><creatorcontrib>Wagner, Trixie</creatorcontrib><creatorcontrib>Walter, Hansrudolf</creatorcontrib><creatorcontrib>Weckbecker, Gisbert</creatorcontrib><creatorcontrib>Zerwes, Hans-Guenter</creatorcontrib><collection>Istex</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thoma, Gebhard</au><au>Nuninger, François</au><au>Schaefer, Marc</au><au>Akyel, Kayhan G</au><au>Albert, Rainer</au><au>Beerli, Christian</au><au>Bruns, Christian</au><au>Francotte, Eric</au><au>Luyten, Marcel</au><au>MacKenzie, Duncan</au><au>Oberer, Lukas</au><au>Streiff, Markus B</au><au>Wagner, Trixie</au><au>Walter, Hansrudolf</au><au>Weckbecker, Gisbert</au><au>Zerwes, Hans-Guenter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Orally Bioavailable Competitive CCR5 Antagonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2004-04-08</date><risdate>2004</risdate><volume>47</volume><issue>8</issue><spage>1939</spage><epage>1955</epage><pages>1939-1955</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure−activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>15055994</pmid><doi>10.1021/jm031046g</doi><tpages>17</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2004-04, Vol.47 (8), p.1939-1955 |
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| subjects | Administration, Oral Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Biological Availability Calcium - metabolism CCR5 Receptor Antagonists Cell Line Chemotaxis, Leukocyte Cricetinae Crystallography, X-Ray Diphenylamine - analogs & derivatives Diphenylamine - chemical synthesis Diphenylamine - chemistry Diphenylamine - pharmacology Humans Immunomodulators In Vitro Techniques Lymphocytes - drug effects Lymphocytes - physiology Macaca fascicularis Medical sciences Mice Molecular Structure Pharmacology. Drug treatments Pyrimidinones - chemical synthesis Pyrimidinones - chemistry Pyrimidinones - pharmacology Radioligand Assay Rats Structure-Activity Relationship |
| title | Orally Bioavailable Competitive CCR5 Antagonists |
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