A Multivalent Approach to the Design and Discovery of Orally Efficacious 5-HT4 Receptor Agonists
5-HT4 receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT4 recep...
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-09, Vol.52 (17), p.5330-5343 |
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| container_title | Journal of medicinal chemistry |
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| creator | McKinnell, R. Murray Armstrong, Scott R Beattie, David T Choi, Seok-Ki Fatheree, Paul R Gendron, Roland A. L Goldblum, Adam Humphrey, Patrick P Long, Daniel D Marquess, Daniel G Shaw, J. P Smith, Jacqueline A. M Turner, S. Derek Vickery, Ross G |
| description | 5-HT4 receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT4 receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a “secondary” binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT4 agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT4 agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT4 agonist for the potential treatment of gastrointestinal motility-related disorders. |
| doi_str_mv | 10.1021/jm900881j |
| format | Article |
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Murray ; Armstrong, Scott R ; Beattie, David T ; Choi, Seok-Ki ; Fatheree, Paul R ; Gendron, Roland A. L ; Goldblum, Adam ; Humphrey, Patrick P ; Long, Daniel D ; Marquess, Daniel G ; Shaw, J. P ; Smith, Jacqueline A. M ; Turner, S. Derek ; Vickery, Ross G</creator><creatorcontrib>McKinnell, R. Murray ; Armstrong, Scott R ; Beattie, David T ; Choi, Seok-Ki ; Fatheree, Paul R ; Gendron, Roland A. L ; Goldblum, Adam ; Humphrey, Patrick P ; Long, Daniel D ; Marquess, Daniel G ; Shaw, J. P ; Smith, Jacqueline A. M ; Turner, S. Derek ; Vickery, Ross G</creatorcontrib><description>5-HT4 receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT4 receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a “secondary” binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT4 agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT4 agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT4 agonist for the potential treatment of gastrointestinal motility-related disorders.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm900881j</identifier><identifier>PMID: 19663444</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Binding Sites ; Biological and medical sciences ; Biological Availability ; Cell Line ; Digestive system ; Dogs ; Drug Design ; Gastrointestinal Diseases - drug therapy ; Humans ; Male ; Medical sciences ; Movement - drug effects ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Piperazines - administration & dosage ; Piperazines - chemical synthesis ; Piperazines - pharmacokinetics ; Piperazines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT4 - metabolism ; Serotonin 5-HT4 Receptor Agonists ; Serotoninergic system ; Substrate Specificity</subject><ispartof>Journal of medicinal chemistry, 2009-09, Vol.52 (17), p.5330-5343</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm900881j$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm900881j$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22098162$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19663444$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McKinnell, R. Murray</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</creatorcontrib><creatorcontrib>Humphrey, Patrick P</creatorcontrib><creatorcontrib>Long, Daniel D</creatorcontrib><creatorcontrib>Marquess, Daniel G</creatorcontrib><creatorcontrib>Shaw, J. P</creatorcontrib><creatorcontrib>Smith, Jacqueline A. M</creatorcontrib><creatorcontrib>Turner, S. Derek</creatorcontrib><creatorcontrib>Vickery, Ross G</creatorcontrib><title>A Multivalent Approach to the Design and Discovery of Orally Efficacious 5-HT4 Receptor Agonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>5-HT4 receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT4 receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a “secondary” binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT4 agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT4 agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT4 agonist for the potential treatment of gastrointestinal motility-related disorders.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Cell Line</subject><subject>Digestive system</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Gastrointestinal Diseases - drug therapy</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Movement - drug effects</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - administration & dosage</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - pharmacokinetics</subject><subject>Piperazines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Serotonin, 5-HT4 - metabolism</subject><subject>Serotonin 5-HT4 Receptor Agonists</subject><subject>Serotoninergic system</subject><subject>Substrate Specificity</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kclOwzAYhC0EoqVw4AWQL3ALeMviY0QLRSqqhMo52M7vNlE2YqdS354gSk9z-TSaBaFbSh4pYfSprCUhSULLMzSlISOBSIg4R1NCGAtYxPgEXTlXEkI4ZfwSTaiMIi6EmKKvFL8PlS_2qoLG47Tr-laZHfYt9jvAc3DFtsGqyfG8cKbdQ3_ArcXrXlXVAS-sLYwyRTs4HAbLjcAfYKDzbY_TbdsUzrtrdGFV5eDmqDP0-bLYPC-D1fr17TldBYpJ4QOaWBvnRsdMW6qZTLg2UkbcGmNFDNqAljqhIZcQKxlyIiG0kYVchCaPNPAZevjzHQt8D-B8Vo-BoapUA2O8LIojTmgoR_DuCA66hjzr-qJW_SH732QE7o-AckZVtleNKdyJY4zIhI6jnjhlXFa2Q9-M_TJKst9PstMn_Ac6yHu4</recordid><startdate>20090910</startdate><enddate>20090910</enddate><creator>McKinnell, R. 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| ispartof | Journal of medicinal chemistry, 2009-09, Vol.52 (17), p.5330-5343 |
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| subjects | Administration, Oral Animals Binding Sites Biological and medical sciences Biological Availability Cell Line Digestive system Dogs Drug Design Gastrointestinal Diseases - drug therapy Humans Male Medical sciences Movement - drug effects Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Piperazines - administration & dosage Piperazines - chemical synthesis Piperazines - pharmacokinetics Piperazines - pharmacology Rats Rats, Sprague-Dawley Receptors, Serotonin, 5-HT4 - metabolism Serotonin 5-HT4 Receptor Agonists Serotoninergic system Substrate Specificity |
| title | A Multivalent Approach to the Design and Discovery of Orally Efficacious 5-HT4 Receptor Agonists |
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