Discovery of potent CCR4 antagonists: Synthesis and structure–activity relationship study of 2,4-diaminoquinazolines
A new series of potent competitive CCR4 antagonists were discovered. Compound 14a showed potent inhibition in the [ 35S]GTPγS-binding assay, and blocked the chemotaxis of human and mouse CCR4-expressing cells. A new series of quinazolines that function as CCR4 antagonists were discovered during the...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2008-07, Vol.16 (14), p.7021-7032 |
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| container_issue | 14 |
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| container_title | Bioorganic & medicinal chemistry |
| container_volume | 16 |
| creator | Yokoyama, Kazuhiro Ishikawa, Noriko Igarashi, Susumu Kawano, Noriyuki Hattori, Kazuyuki Miyazaki, Takahiro Ogino, Shin-ichi Matsumoto, Yuzo Takeuchi, Makoto Ohta, Mitsuaki |
| description | A new series of potent competitive CCR4 antagonists were discovered. Compound
14a showed potent inhibition in the [
35S]GTPγS-binding assay, and blocked the chemotaxis of human and mouse CCR4-expressing cells.
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure–activity relationships and led the identification of 2-(1,4′-bipiperidine-1′-yl)-
N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine
14a, which showed potent inhibition in the [
35S]GTPγS-binding assay (IC
50
=
18
nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC
50
=
140
nM, 39
nM). |
| doi_str_mv | 10.1016/j.bmc.2008.05.036 |
| format | Article |
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14a showed potent inhibition in the [
35S]GTPγS-binding assay, and blocked the chemotaxis of human and mouse CCR4-expressing cells.
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure–activity relationships and led the identification of 2-(1,4′-bipiperidine-1′-yl)-
N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine
14a, which showed potent inhibition in the [
35S]GTPγS-binding assay (IC
50
=
18
nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC
50
=
140
nM, 39
nM).</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2008.05.036</identifier><identifier>PMID: 18539035</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>2,4-Diaminoquinazolines ; Animals ; Antagonists ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Chemokine receptor 4 (CCR4) ; Chemotaxis - drug effects ; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism ; Humans ; Inflammatory disease ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Quinazolines - chemical synthesis ; Quinazolines - pharmacology ; Receptors, CCR4 - antagonists & inhibitors ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry, 2008-07, Vol.16 (14), p.7021-7032</ispartof><rights>2008 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-4619cd31d538948a957419594681c0715b72953682fcea6ff74fcc54f11433853</citedby><cites>FETCH-LOGICAL-c478t-4619cd31d538948a957419594681c0715b72953682fcea6ff74fcc54f11433853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089608004689$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20778158$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18539035$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yokoyama, Kazuhiro</creatorcontrib><creatorcontrib>Ishikawa, Noriko</creatorcontrib><creatorcontrib>Igarashi, Susumu</creatorcontrib><creatorcontrib>Kawano, Noriyuki</creatorcontrib><creatorcontrib>Hattori, Kazuyuki</creatorcontrib><creatorcontrib>Miyazaki, Takahiro</creatorcontrib><creatorcontrib>Ogino, Shin-ichi</creatorcontrib><creatorcontrib>Matsumoto, Yuzo</creatorcontrib><creatorcontrib>Takeuchi, Makoto</creatorcontrib><creatorcontrib>Ohta, Mitsuaki</creatorcontrib><title>Discovery of potent CCR4 antagonists: Synthesis and structure–activity relationship study of 2,4-diaminoquinazolines</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>A new series of potent competitive CCR4 antagonists were discovered. Compound
14a showed potent inhibition in the [
35S]GTPγS-binding assay, and blocked the chemotaxis of human and mouse CCR4-expressing cells.
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure–activity relationships and led the identification of 2-(1,4′-bipiperidine-1′-yl)-
N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine
14a, which showed potent inhibition in the [
35S]GTPγS-binding assay (IC
50
=
18
nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC
50
=
140
nM, 39
nM).</description><subject>2,4-Diaminoquinazolines</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Chemokine receptor 4 (CCR4)</subject><subject>Chemotaxis - drug effects</subject><subject>Guanosine 5'-O-(3-Thiotriphosphate) - metabolism</subject><subject>Humans</subject><subject>Inflammatory disease</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinazolines - chemical synthesis</subject><subject>Quinazolines - pharmacology</subject><subject>Receptors, CCR4 - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUuO1DAQhi0EYnoGDsAGZQMrEsrxIzazQs3wkEZC4rG23I7NuJXYje201Ky4AzfkJHjoFuxgVZL11V9V_hB6hKHDgPnzbbeZTdcDiA5YB4TfQStMOW0JkfguWoHkogUh-Rk6z3kLAD2V-D46w4IRCYSt0P6VzybubTo00TW7WGwozXr9gTY6FP0lBp9LftF8PIRyY7PP9XlsckmLKUuyP7__0Kb4vS-HJtlJFx9DvvG7Sizj78T-GW1Hr2cf4tfFB_0tTj7Y_ADdc3rK9uGpXqDPr68-rd-21-_fvFu_vG4NHURpKcfSjASPjAhJhZZsoFgySbnABgbMNkMvGeGid8Zq7txAnTGMOowpIfXIC_T0mLtLdb7NRc31XjtNOti4ZMUloRwG8l-wTgWGOa8gPoImxZyTdWqX_KzTQWFQt1bUVlUr6taKAqaqldrz-BS-bGY7_u04aajAkxOgs9GTSzoYn_9wPQyDwExU7vLI2fpne2-TysbbYOzokzVFjdH_Y41fHqGrgw</recordid><startdate>20080715</startdate><enddate>20080715</enddate><creator>Yokoyama, Kazuhiro</creator><creator>Ishikawa, Noriko</creator><creator>Igarashi, Susumu</creator><creator>Kawano, Noriyuki</creator><creator>Hattori, Kazuyuki</creator><creator>Miyazaki, Takahiro</creator><creator>Ogino, Shin-ichi</creator><creator>Matsumoto, Yuzo</creator><creator>Takeuchi, Makoto</creator><creator>Ohta, Mitsuaki</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20080715</creationdate><title>Discovery of potent CCR4 antagonists: Synthesis and structure–activity relationship study of 2,4-diaminoquinazolines</title><author>Yokoyama, Kazuhiro ; Ishikawa, Noriko ; Igarashi, Susumu ; Kawano, Noriyuki ; Hattori, Kazuyuki ; Miyazaki, Takahiro ; Ogino, Shin-ichi ; Matsumoto, Yuzo ; Takeuchi, Makoto ; Ohta, Mitsuaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-4619cd31d538948a957419594681c0715b72953682fcea6ff74fcc54f11433853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>2,4-Diaminoquinazolines</topic><topic>Animals</topic><topic>Antagonists</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Chemokine receptor 4 (CCR4)</topic><topic>Chemotaxis - drug effects</topic><topic>Guanosine 5'-O-(3-Thiotriphosphate) - metabolism</topic><topic>Humans</topic><topic>Inflammatory disease</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Quinazolines - chemical synthesis</topic><topic>Quinazolines - pharmacology</topic><topic>Receptors, CCR4 - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yokoyama, Kazuhiro</creatorcontrib><creatorcontrib>Ishikawa, Noriko</creatorcontrib><creatorcontrib>Igarashi, Susumu</creatorcontrib><creatorcontrib>Kawano, Noriyuki</creatorcontrib><creatorcontrib>Hattori, Kazuyuki</creatorcontrib><creatorcontrib>Miyazaki, Takahiro</creatorcontrib><creatorcontrib>Ogino, Shin-ichi</creatorcontrib><creatorcontrib>Matsumoto, Yuzo</creatorcontrib><creatorcontrib>Takeuchi, Makoto</creatorcontrib><creatorcontrib>Ohta, Mitsuaki</creatorcontrib><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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yokoyama, Kazuhiro</au><au>Ishikawa, Noriko</au><au>Igarashi, Susumu</au><au>Kawano, Noriyuki</au><au>Hattori, Kazuyuki</au><au>Miyazaki, Takahiro</au><au>Ogino, Shin-ichi</au><au>Matsumoto, Yuzo</au><au>Takeuchi, Makoto</au><au>Ohta, Mitsuaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of potent CCR4 antagonists: Synthesis and structure–activity relationship study of 2,4-diaminoquinazolines</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2008-07-15</date><risdate>2008</risdate><volume>16</volume><issue>14</issue><spage>7021</spage><epage>7032</epage><pages>7021-7032</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>A new series of potent competitive CCR4 antagonists were discovered. Compound
14a showed potent inhibition in the [
35S]GTPγS-binding assay, and blocked the chemotaxis of human and mouse CCR4-expressing cells.
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure–activity relationships and led the identification of 2-(1,4′-bipiperidine-1′-yl)-
N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine
14a, which showed potent inhibition in the [
35S]GTPγS-binding assay (IC
50
=
18
nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC
50
=
140
nM, 39
nM).</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>18539035</pmid><doi>10.1016/j.bmc.2008.05.036</doi><tpages>12</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2008-07, Vol.16 (14), p.7021-7032 |
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| language | eng |
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| subjects | 2,4-Diaminoquinazolines Animals Antagonists Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Chemokine receptor 4 (CCR4) Chemotaxis - drug effects Guanosine 5'-O-(3-Thiotriphosphate) - metabolism Humans Inflammatory disease Medical sciences Mice Pharmacology. Drug treatments Quinazolines - chemical synthesis Quinazolines - pharmacology Receptors, CCR4 - antagonists & inhibitors Structure-Activity Relationship |
| title | Discovery of potent CCR4 antagonists: Synthesis and structure–activity relationship study of 2,4-diaminoquinazolines |
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