Design of a New Class of Orally Active Fibrinogen Receptor Antagonists
The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quick...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-07, Vol.41 (14), p.2492-2502 |
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| container_title | Journal of medicinal chemistry |
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| creator | Klein, Scott I Molino, Bruce F Czekaj, Mark Gardner, Charles J Chu, Valeria Brown, Karen Sabatino, Ralph D Bostwick, Jeffrey S Kasiewski, Charles Bentley, Ross Windisch, Vincent Perrone, Mark Dunwiddie, Christopher T Leadley, Robert J |
| description | The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action. |
| doi_str_mv | 10.1021/jm9801096 |
| format | Article |
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Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm9801096</identifier><identifier>PMID: 9651154</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Biological and medical sciences ; Blood Platelets - drug effects ; Blood. Blood coagulation. Reticuloendothelial system ; Cell Adhesion - drug effects ; Dogs ; Endothelium, Vascular - cytology ; Endothelium, Vascular - drug effects ; Female ; Humans ; In Vitro Techniques ; Male ; Medical sciences ; Oligopeptides - administration & dosage ; Oligopeptides - chemical synthesis ; Oligopeptides - metabolism ; Oligopeptides - pharmacology ; Pharmacology. Drug treatments ; Piperidines - administration & dosage ; Piperidines - chemical synthesis ; Piperidines - metabolism ; Piperidines - pharmacology ; Platelet Activation ; Platelet Aggregation - drug effects ; Platelet Aggregation Inhibitors - administration & dosage ; Platelet Aggregation Inhibitors - chemical synthesis ; Platelet Aggregation Inhibitors - metabolism ; Platelet Aggregation Inhibitors - pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors ; Structure-Activity Relationship ; Umbilical Veins - cytology ; Umbilical Veins - drug effects</subject><ispartof>Journal of medicinal chemistry, 1998-07, Vol.41 (14), p.2492-2502</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a404t-2ac28bf7457ab18d968ee42a1eae8736ef08d5b9fd6c88a7b939efbc2b9d6dae3</citedby><cites>FETCH-LOGICAL-a404t-2ac28bf7457ab18d968ee42a1eae8736ef08d5b9fd6c88a7b939efbc2b9d6dae3</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/jm9801096$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm9801096$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2322916$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9651154$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Klein, Scott I</creatorcontrib><creatorcontrib>Molino, Bruce F</creatorcontrib><creatorcontrib>Czekaj, Mark</creatorcontrib><creatorcontrib>Gardner, Charles J</creatorcontrib><creatorcontrib>Chu, Valeria</creatorcontrib><creatorcontrib>Brown, Karen</creatorcontrib><creatorcontrib>Sabatino, Ralph D</creatorcontrib><creatorcontrib>Bostwick, Jeffrey S</creatorcontrib><creatorcontrib>Kasiewski, Charles</creatorcontrib><creatorcontrib>Bentley, Ross</creatorcontrib><creatorcontrib>Windisch, Vincent</creatorcontrib><creatorcontrib>Perrone, Mark</creatorcontrib><creatorcontrib>Dunwiddie, Christopher T</creatorcontrib><creatorcontrib>Leadley, Robert J</creatorcontrib><title>Design of a New Class of Orally Active Fibrinogen Receptor Antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Platelets - drug effects</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Cell Adhesion - drug effects</subject><subject>Dogs</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Oligopeptides - administration & dosage</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - metabolism</subject><subject>Oligopeptides - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperidines - administration & dosage</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - metabolism</subject><subject>Piperidines - pharmacology</subject><subject>Platelet Activation</subject><subject>Platelet Aggregation - drug effects</subject><subject>Platelet Aggregation Inhibitors - administration & dosage</subject><subject>Platelet Aggregation Inhibitors - chemical synthesis</subject><subject>Platelet Aggregation Inhibitors - metabolism</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Umbilical Veins - cytology</subject><subject>Umbilical Veins - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtLw0AUhQdRan0s_AFCFiq4iM4jk8wsSzU-UdGK4Ga4mdyU1DSpM6mPf29KS1euLofzcbh8hBwwesYoZ-eTqVaUUR1vkD6TnIaRotEm6VPKechjLrbJjvcTSqlgXPRIT8eSMRn1SXqBvhzXQVMEEDzgdzCswPtFfHRQVb_BwLblFwZpmbmybsZYB89ocdY2LhjULYybuvSt3yNbBVQe91d3l7yml6PhdXj_eHUzHNyHENGoDTlYrrIiiWQCGVO5jhVixIEhoEpEjAVVucx0kcdWKUgyLTQWmeWZzuMcUOySk-XuzDWfc_StmZbeYlVBjc3cm0RrJSOhO_B0CVrXeO-wMDNXTsH9GkbNwplZO-vYw9XoPJtiviZXkrr-aNWDt1AVDmpb-jXGBeeaLWbCJdYJwZ91De7DxIlIpBk9vZj3u1Smt-zNyI4_XvJgvZk0c1d35v557w8rqo33</recordid><startdate>19980702</startdate><enddate>19980702</enddate><creator>Klein, Scott I</creator><creator>Molino, Bruce F</creator><creator>Czekaj, Mark</creator><creator>Gardner, Charles J</creator><creator>Chu, Valeria</creator><creator>Brown, Karen</creator><creator>Sabatino, Ralph D</creator><creator>Bostwick, Jeffrey S</creator><creator>Kasiewski, Charles</creator><creator>Bentley, Ross</creator><creator>Windisch, Vincent</creator><creator>Perrone, Mark</creator><creator>Dunwiddie, Christopher T</creator><creator>Leadley, Robert J</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>19980702</creationdate><title>Design of a New Class of Orally Active Fibrinogen Receptor Antagonists</title><author>Klein, Scott I ; Molino, Bruce F ; Czekaj, Mark ; Gardner, Charles J ; Chu, Valeria ; Brown, Karen ; Sabatino, Ralph D ; Bostwick, Jeffrey S ; Kasiewski, Charles ; Bentley, Ross ; Windisch, Vincent ; Perrone, Mark ; Dunwiddie, Christopher T ; Leadley, Robert J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a404t-2ac28bf7457ab18d968ee42a1eae8736ef08d5b9fd6c88a7b939efbc2b9d6dae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Platelets - drug effects</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Cell Adhesion - drug effects</topic><topic>Dogs</topic><topic>Endothelium, Vascular - cytology</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Oligopeptides - administration & dosage</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - metabolism</topic><topic>Oligopeptides - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidines - administration & dosage</topic><topic>Piperidines - chemical synthesis</topic><topic>Piperidines - metabolism</topic><topic>Piperidines - pharmacology</topic><topic>Platelet Activation</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation Inhibitors - administration & dosage</topic><topic>Platelet Aggregation Inhibitors - chemical synthesis</topic><topic>Platelet Aggregation Inhibitors - metabolism</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Umbilical Veins - cytology</topic><topic>Umbilical Veins - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Klein, Scott I</creatorcontrib><creatorcontrib>Molino, Bruce F</creatorcontrib><creatorcontrib>Czekaj, Mark</creatorcontrib><creatorcontrib>Gardner, Charles J</creatorcontrib><creatorcontrib>Chu, Valeria</creatorcontrib><creatorcontrib>Brown, Karen</creatorcontrib><creatorcontrib>Sabatino, Ralph D</creatorcontrib><creatorcontrib>Bostwick, Jeffrey S</creatorcontrib><creatorcontrib>Kasiewski, Charles</creatorcontrib><creatorcontrib>Bentley, Ross</creatorcontrib><creatorcontrib>Windisch, Vincent</creatorcontrib><creatorcontrib>Perrone, Mark</creatorcontrib><creatorcontrib>Dunwiddie, Christopher T</creatorcontrib><creatorcontrib>Leadley, Robert J</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>Klein, Scott I</au><au>Molino, Bruce F</au><au>Czekaj, Mark</au><au>Gardner, Charles J</au><au>Chu, Valeria</au><au>Brown, Karen</au><au>Sabatino, Ralph D</au><au>Bostwick, Jeffrey S</au><au>Kasiewski, Charles</au><au>Bentley, Ross</au><au>Windisch, Vincent</au><au>Perrone, Mark</au><au>Dunwiddie, Christopher T</au><au>Leadley, Robert J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design of a New Class of Orally Active Fibrinogen Receptor Antagonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-07-02</date><risdate>1998</risdate><volume>41</volume><issue>14</issue><spage>2492</spage><epage>2502</epage><pages>2492-2502</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9651154</pmid><doi>10.1021/jm9801096</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1998-07, Vol.41 (14), p.2492-2502 |
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| subjects | Administration, Oral Animals Biological and medical sciences Blood Platelets - drug effects Blood. Blood coagulation. Reticuloendothelial system Cell Adhesion - drug effects Dogs Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Female Humans In Vitro Techniques Male Medical sciences Oligopeptides - administration & dosage Oligopeptides - chemical synthesis Oligopeptides - metabolism Oligopeptides - pharmacology Pharmacology. Drug treatments Piperidines - administration & dosage Piperidines - chemical synthesis Piperidines - metabolism Piperidines - pharmacology Platelet Activation Platelet Aggregation - drug effects Platelet Aggregation Inhibitors - administration & dosage Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - metabolism Platelet Aggregation Inhibitors - pharmacology Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors Structure-Activity Relationship Umbilical Veins - cytology Umbilical Veins - drug effects |
| title | Design of a New Class of Orally Active Fibrinogen Receptor Antagonists |
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