Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: Clinical compound TD-2749
Further application of our multivalent approach to drug discovery directed to 5-HT4 receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT4 receptor, selectiv...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (14), p.4849-4853 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Long, Daniel D. Armstrong, Scott R. Beattie, David T. Choi, Seok-Ki Fatheree, Paul R. Gendron, Roland A.L. Goldblum, Adam A. Humphrey, Patrick P. Marquess, Daniel G. Shaw, Jeng-Pyng Smith, Jacqueline A.M. Derek Turner, S. Vickery, Ross G. |
| description | Further application of our multivalent approach to drug discovery directed to 5-HT4 receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT4 receptor, selectivity over the 5-HT3 receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749. |
| doi_str_mv | 10.1016/j.bmcl.2012.05.034 |
| format | Article |
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Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT4 receptor, selectivity over the 5-HT3 receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.05.034</identifier><identifier>PMID: 22683222</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>5-HT4 receptor agonist ; Administration, Oral ; Alzheimer’s ; Animals ; Biological and medical sciences ; Cell Line ; Drug Discovery ; GI motility ; Heterocyclic Compounds - administration & dosage ; Heterocyclic Compounds - chemistry ; Heterocyclic Compounds - pharmacokinetics ; Humans ; Male ; Medical sciences ; Molecular Structure ; Multivalent approach ; Organ Specificity ; Pharmacology. Drug treatments ; Piperazines - administration & dosage ; Piperazines - chemistry ; Piperazines - pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Serotonin 5-HT4 Receptor Agonists - administration & dosage ; Serotonin 5-HT4 Receptor Agonists - chemistry ; Serotonin 5-HT4 Receptor Agonists - pharmacokinetics ; Structure-Activity Relationship ; TD-2749</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-07, Vol.22 (14), p.4849-4853</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-306d2ae69ad600757982aad163fb8623b03b90806d0f0ac1be2c3574db01e7ec3</citedby><cites>FETCH-LOGICAL-c386t-306d2ae69ad600757982aad163fb8623b03b90806d0f0ac1be2c3574db01e7ec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X12006373$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26151508$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22683222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Long, Daniel D.</creatorcontrib><creatorcontrib>Armstrong, Scott R.</creatorcontrib><creatorcontrib>Beattie, David T.</creatorcontrib><creatorcontrib>Choi, Seok-Ki</creatorcontrib><creatorcontrib>Fatheree, Paul R.</creatorcontrib><creatorcontrib>Gendron, Roland A.L.</creatorcontrib><creatorcontrib>Goldblum, Adam A.</creatorcontrib><creatorcontrib>Humphrey, Patrick P.</creatorcontrib><creatorcontrib>Marquess, Daniel G.</creatorcontrib><creatorcontrib>Shaw, Jeng-Pyng</creatorcontrib><creatorcontrib>Smith, Jacqueline A.M.</creatorcontrib><creatorcontrib>Derek Turner, S.</creatorcontrib><creatorcontrib>Vickery, Ross G.</creatorcontrib><title>Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: Clinical compound TD-2749</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Further application of our multivalent approach to drug discovery directed to 5-HT4 receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT4 receptor, selectivity over the 5-HT3 receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.</description><subject>5-HT4 receptor agonist</subject><subject>Administration, Oral</subject><subject>Alzheimer’s</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Drug Discovery</subject><subject>GI motility</subject><subject>Heterocyclic Compounds - administration & dosage</subject><subject>Heterocyclic Compounds - chemistry</subject><subject>Heterocyclic Compounds - pharmacokinetics</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Multivalent approach</subject><subject>Organ Specificity</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - administration & dosage</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacokinetics</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Serotonin 5-HT4 Receptor Agonists - administration & dosage</subject><subject>Serotonin 5-HT4 Receptor Agonists - chemistry</subject><subject>Serotonin 5-HT4 Receptor Agonists - pharmacokinetics</subject><subject>Structure-Activity Relationship</subject><subject>TD-2749</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi0EokvhD3BAviBxIOn4I06CekFboJUqcVkkbpbjTLpekjjY2Uh74L_j1S701tNcnvedmYeQtwxyBkxd7fJmsH3OgfEcihyEfEZWTCqZCQnFc7KCWkFW1fLnBXkV4w6ASZDyJbngXFWCc74if25ctH7BcPhIfTA9nbYmDMb6X27E2dlIzdhSN9LFLZ5i1zlr7IH6jhq6dQ_b_kAj9mhntyAtstuNpAEtTrMP1Dz40cX5E133bky5nlo_TH6fCjc3GS9l_Zq86Ewf8c15XpIfX79s1rfZ_fdvd-vP95kVlZozAarlBlVtWgVQFmVdcWNapkTXVIqLBkRTQ5Uo6MBY1iC3oihl2wDDEq24JB9OvVPwv_cYZz2kt7HvzYh-HzUDLnhdiaJKKD-hNvgYA3Z6Cm4w4ZAgfdSud_qoXR-1ayh00p5C7879-2bA9n_kn-cEvD8DJiYRXTCjdfGRU6xgBRy3X584TDYWh0FH63C02Lqkddatd0_d8RfLYKAD</recordid><startdate>20120715</startdate><enddate>20120715</enddate><creator>Long, Daniel D.</creator><creator>Armstrong, Scott R.</creator><creator>Beattie, David T.</creator><creator>Choi, Seok-Ki</creator><creator>Fatheree, Paul R.</creator><creator>Gendron, Roland A.L.</creator><creator>Goldblum, Adam A.</creator><creator>Humphrey, Patrick P.</creator><creator>Marquess, Daniel G.</creator><creator>Shaw, Jeng-Pyng</creator><creator>Smith, Jacqueline A.M.</creator><creator>Derek Turner, S.</creator><creator>Vickery, Ross G.</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>7X8</scope></search><sort><creationdate>20120715</creationdate><title>Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: Clinical compound TD-2749</title><author>Long, Daniel D. ; Armstrong, Scott R. ; Beattie, David T. ; Choi, Seok-Ki ; Fatheree, Paul R. ; Gendron, Roland A.L. ; Goldblum, Adam A. ; Humphrey, Patrick P. ; Marquess, Daniel G. ; Shaw, Jeng-Pyng ; Smith, Jacqueline A.M. ; Derek Turner, S. ; Vickery, Ross G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-306d2ae69ad600757982aad163fb8623b03b90806d0f0ac1be2c3574db01e7ec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>5-HT4 receptor agonist</topic><topic>Administration, Oral</topic><topic>Alzheimer’s</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Drug Discovery</topic><topic>GI motility</topic><topic>Heterocyclic Compounds - administration & dosage</topic><topic>Heterocyclic Compounds - chemistry</topic><topic>Heterocyclic Compounds - pharmacokinetics</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Multivalent approach</topic><topic>Organ Specificity</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - administration & dosage</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacokinetics</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Serotonin 5-HT4 Receptor Agonists - administration & dosage</topic><topic>Serotonin 5-HT4 Receptor Agonists - chemistry</topic><topic>Serotonin 5-HT4 Receptor Agonists - pharmacokinetics</topic><topic>Structure-Activity Relationship</topic><topic>TD-2749</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Long, Daniel D.</creatorcontrib><creatorcontrib>Armstrong, Scott R.</creatorcontrib><creatorcontrib>Beattie, David T.</creatorcontrib><creatorcontrib>Choi, Seok-Ki</creatorcontrib><creatorcontrib>Fatheree, Paul R.</creatorcontrib><creatorcontrib>Gendron, Roland A.L.</creatorcontrib><creatorcontrib>Goldblum, Adam A.</creatorcontrib><creatorcontrib>Humphrey, Patrick P.</creatorcontrib><creatorcontrib>Marquess, Daniel G.</creatorcontrib><creatorcontrib>Shaw, Jeng-Pyng</creatorcontrib><creatorcontrib>Smith, Jacqueline A.M.</creatorcontrib><creatorcontrib>Derek Turner, S.</creatorcontrib><creatorcontrib>Vickery, Ross G.</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>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Long, Daniel D.</au><au>Armstrong, Scott R.</au><au>Beattie, David T.</au><au>Choi, Seok-Ki</au><au>Fatheree, Paul R.</au><au>Gendron, Roland A.L.</au><au>Goldblum, Adam A.</au><au>Humphrey, Patrick P.</au><au>Marquess, Daniel G.</au><au>Shaw, Jeng-Pyng</au><au>Smith, Jacqueline A.M.</au><au>Derek Turner, S.</au><au>Vickery, Ross G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: Clinical compound TD-2749</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-07-15</date><risdate>2012</risdate><volume>22</volume><issue>14</issue><spage>4849</spage><epage>4853</epage><pages>4849-4853</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Further application of our multivalent approach to drug discovery directed to 5-HT4 receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT4 receptor, selectivity over the 5-HT3 receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22683222</pmid><doi>10.1016/j.bmcl.2012.05.034</doi><tpages>5</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-07, Vol.22 (14), p.4849-4853 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 5-HT4 receptor agonist Administration, Oral Alzheimer’s Animals Biological and medical sciences Cell Line Drug Discovery GI motility Heterocyclic Compounds - administration & dosage Heterocyclic Compounds - chemistry Heterocyclic Compounds - pharmacokinetics Humans Male Medical sciences Molecular Structure Multivalent approach Organ Specificity Pharmacology. Drug treatments Piperazines - administration & dosage Piperazines - chemistry Piperazines - pharmacokinetics Rats Rats, Sprague-Dawley Serotonin 5-HT4 Receptor Agonists - administration & dosage Serotonin 5-HT4 Receptor Agonists - chemistry Serotonin 5-HT4 Receptor Agonists - pharmacokinetics Structure-Activity Relationship TD-2749 |
| title | Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: Clinical compound TD-2749 |
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