Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile
We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)meth...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (9), p.2626-2630 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Hughes, Robert O Rogier, D.J Devraj, Rajesh Zheng, Changsheng Cao, Ganfeng Feng, Hao Xia, Michael Anand, Rajan Xing, Li Glenn, Joseph Zhang, Ke Covington, Maryanne Morton, Philip A Hutzler, J. Matthew Davis, John W., II Scherle, Peggy Baribaud, Fred Bahinski, Anthony Mo, Zun-Li Newton, Robert Metcalf, Brian Xue, Chu-Biao |
| description | We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35–45mg BID and a CV-TI=3800-fold. |
| doi_str_mv | 10.1016/j.bmcl.2011.01.034 |
| format | Article |
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This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35–45mg BID and a CV-TI=3800-fold.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.01.034</identifier><identifier>PMID: 21315584</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>antagonists ; Anti-Inflammatory Agents - chemistry ; Anti-Inflammatory Agents - pharmacokinetics ; Anti-Inflammatory Agents - pharmacology ; Biological Assay ; chemistry ; Humans ; Inhibitory Concentration 50 ; Microsomes - drug effects ; Microsomes - metabolism ; Models, Molecular ; Molecular Structure ; Piperazines - chemistry ; Piperazines - pharmacokinetics ; Piperazines - pharmacology ; Protein Binding - drug effects ; Pyridazines - chemistry ; Pyridazines - pharmacokinetics ; Pyridazines - pharmacology ; Receptors, CCR2 - agonists ; Receptors, CCR2 - blood ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-05, Vol.21 (9), p.2626-2630</ispartof><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c326t-63f81abe8403a73ab016e3bd967201dd5dc48c08a3f541611a390c5997096f63</citedby><cites>FETCH-LOGICAL-c326t-63f81abe8403a73ab016e3bd967201dd5dc48c08a3f541611a390c5997096f63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21315584$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hughes, Robert O</creatorcontrib><creatorcontrib>Rogier, D.J</creatorcontrib><creatorcontrib>Devraj, Rajesh</creatorcontrib><creatorcontrib>Zheng, Changsheng</creatorcontrib><creatorcontrib>Cao, Ganfeng</creatorcontrib><creatorcontrib>Feng, Hao</creatorcontrib><creatorcontrib>Xia, Michael</creatorcontrib><creatorcontrib>Anand, Rajan</creatorcontrib><creatorcontrib>Xing, Li</creatorcontrib><creatorcontrib>Glenn, Joseph</creatorcontrib><creatorcontrib>Zhang, Ke</creatorcontrib><creatorcontrib>Covington, Maryanne</creatorcontrib><creatorcontrib>Morton, Philip A</creatorcontrib><creatorcontrib>Hutzler, J. Matthew</creatorcontrib><creatorcontrib>Davis, John W., II</creatorcontrib><creatorcontrib>Scherle, Peggy</creatorcontrib><creatorcontrib>Baribaud, Fred</creatorcontrib><creatorcontrib>Bahinski, Anthony</creatorcontrib><creatorcontrib>Mo, Zun-Li</creatorcontrib><creatorcontrib>Newton, Robert</creatorcontrib><creatorcontrib>Metcalf, Brian</creatorcontrib><creatorcontrib>Xue, Chu-Biao</creatorcontrib><title>Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. 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Matthew</creator><creator>Davis, John W., II</creator><creator>Scherle, Peggy</creator><creator>Baribaud, Fred</creator><creator>Bahinski, Anthony</creator><creator>Mo, Zun-Li</creator><creator>Newton, Robert</creator><creator>Metcalf, Brian</creator><creator>Xue, Chu-Biao</creator><general>Elsevier Ltd</general><scope>FBQ</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>20110501</creationdate><title>Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile</title><author>Hughes, Robert O ; Rogier, D.J ; Devraj, Rajesh ; Zheng, Changsheng ; Cao, Ganfeng ; Feng, Hao ; Xia, Michael ; Anand, Rajan ; Xing, Li ; Glenn, Joseph ; Zhang, Ke ; Covington, Maryanne ; Morton, Philip A ; Hutzler, J. 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Matthew</au><au>Davis, John W., II</au><au>Scherle, Peggy</au><au>Baribaud, Fred</au><au>Bahinski, Anthony</au><au>Mo, Zun-Li</au><au>Newton, Robert</au><au>Metcalf, Brian</au><au>Xue, Chu-Biao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>21</volume><issue>9</issue><spage>2626</spage><epage>2630</epage><pages>2626-2630</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35–45mg BID and a CV-TI=3800-fold.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>21315584</pmid><doi>10.1016/j.bmcl.2011.01.034</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-05, Vol.21 (9), p.2626-2630 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_863432173 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | antagonists Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacokinetics Anti-Inflammatory Agents - pharmacology Biological Assay chemistry Humans Inhibitory Concentration 50 Microsomes - drug effects Microsomes - metabolism Models, Molecular Molecular Structure Piperazines - chemistry Piperazines - pharmacokinetics Piperazines - pharmacology Protein Binding - drug effects Pyridazines - chemistry Pyridazines - pharmacokinetics Pyridazines - pharmacology Receptors, CCR2 - agonists Receptors, CCR2 - blood Structure-Activity Relationship |
| title | Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile |
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