Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor
Peptide mimetics of the RGDF sequence in which Arg-Gly has been replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carbox...
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| Veröffentlicht in: | Journal of medicinal chemistry 1993-06, Vol.36 (13), p.1811-1819 |
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| container_issue | 13 |
| container_start_page | 1811 |
| container_title | Journal of medicinal chemistry |
| container_volume | 36 |
| creator | Zablocki, Jeffery A Miyano, Masateru Garland, Robert B Pireh, Daisy Schretzman, Lori Rao, Shashidhar N Lindmark, Richard J Panzer-Knodle, Susan G Nicholson, Nancy S |
| description | Peptide mimetics of the RGDF sequence in which Arg-Gly has been replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carboxylate of the receptor which could explain the dramatic increase in potency upon replacement with benzamidine. This hypothesis is supported by the observation of low inhibitory potency of the corresponding benzylamine (18) and no activity with the corresponding imidazoline derivative (19); plus, ab initio calculations on the respective complexes suggest that the benzamidine-carboxylate is more favorable than the guanidine-carboxylate interaction. The ED50 for the inhibition of ex vivo collagen induced platelet aggregation in the dog for SC-52012 (1) was 0.32 microgram/kg/min by iv infusion with a pharmacodynamic half-life for recovery of approximately 40 min. |
| doi_str_mv | 10.1021/jm00065a003 |
| format | Article |
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A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Zablocki, Jeffery A ; Miyano, Masateru ; Garland, Robert B ; Pireh, Daisy ; Schretzman, Lori ; Rao, Shashidhar N ; Lindmark, Richard J ; Panzer-Knodle, Susan G ; Nicholson, Nancy S</creator><creatorcontrib>Zablocki, Jeffery A ; Miyano, Masateru ; Garland, Robert B ; Pireh, Daisy ; Schretzman, Lori ; Rao, Shashidhar N ; Lindmark, Richard J ; Panzer-Knodle, Susan G ; Nicholson, Nancy S</creatorcontrib><description>Peptide mimetics of the RGDF sequence in which Arg-Gly has been replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carboxylate of the receptor which could explain the dramatic increase in potency upon replacement with benzamidine. This hypothesis is supported by the observation of low inhibitory potency of the corresponding benzylamine (18) and no activity with the corresponding imidazoline derivative (19); plus, ab initio calculations on the respective complexes suggest that the benzamidine-carboxylate is more favorable than the guanidine-carboxylate interaction. The ED50 for the inhibition of ex vivo collagen induced platelet aggregation in the dog for SC-52012 (1) was 0.32 microgram/kg/min by iv infusion with a pharmacodynamic half-life for recovery of approximately 40 min.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00065a003</identifier><identifier>PMID: 8515420</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amino Acid Sequence ; Animals ; Benzamidines - chemical synthesis ; Benzamidines - metabolism ; Benzamidines - pharmacology ; Chemistry ; Dogs ; Exact sciences and technology ; Fibrinogen - chemistry ; Fibrinogen - metabolism ; Guanidine ; Guanidines - metabolism ; Humans ; In Vitro Techniques ; Models, Chemical ; Molecular Sequence Data ; Oligopeptides - chemical synthesis ; Oligopeptides - metabolism ; Oligopeptides - pharmacology ; Organic chemistry ; Peptides ; Platelet Aggregation Inhibitors - chemical synthesis ; Platelet Aggregation Inhibitors - metabolism ; Platelet Aggregation Inhibitors - pharmacology ; Platelet Membrane Glycoproteins - metabolism ; Preparations and properties ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1993-06, Vol.36 (13), p.1811-1819</ispartof><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-781a790243133a3eb485275d59a7eae0b0d77283ab4871bc402ea6606c077df93</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00065a003$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00065a003$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4810156$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8515420$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zablocki, Jeffery A</creatorcontrib><creatorcontrib>Miyano, Masateru</creatorcontrib><creatorcontrib>Garland, Robert B</creatorcontrib><creatorcontrib>Pireh, Daisy</creatorcontrib><creatorcontrib>Schretzman, Lori</creatorcontrib><creatorcontrib>Rao, Shashidhar N</creatorcontrib><creatorcontrib>Lindmark, Richard J</creatorcontrib><creatorcontrib>Panzer-Knodle, Susan G</creatorcontrib><creatorcontrib>Nicholson, Nancy S</creatorcontrib><title>Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Peptide mimetics of the RGDF sequence in which Arg-Gly has been replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carboxylate of the receptor which could explain the dramatic increase in potency upon replacement with benzamidine. This hypothesis is supported by the observation of low inhibitory potency of the corresponding benzylamine (18) and no activity with the corresponding imidazoline derivative (19); plus, ab initio calculations on the respective complexes suggest that the benzamidine-carboxylate is more favorable than the guanidine-carboxylate interaction. The ED50 for the inhibition of ex vivo collagen induced platelet aggregation in the dog for SC-52012 (1) was 0.32 microgram/kg/min by iv infusion with a pharmacodynamic half-life for recovery of approximately 40 min.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Benzamidines - chemical synthesis</subject><subject>Benzamidines - metabolism</subject><subject>Benzamidines - pharmacology</subject><subject>Chemistry</subject><subject>Dogs</subject><subject>Exact sciences and technology</subject><subject>Fibrinogen - chemistry</subject><subject>Fibrinogen - metabolism</subject><subject>Guanidine</subject><subject>Guanidines - metabolism</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Models, Chemical</subject><subject>Molecular Sequence Data</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - metabolism</subject><subject>Oligopeptides - pharmacology</subject><subject>Organic chemistry</subject><subject>Peptides</subject><subject>Platelet Aggregation Inhibitors - chemical synthesis</subject><subject>Platelet Aggregation Inhibitors - metabolism</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Platelet Membrane Glycoproteins - metabolism</subject><subject>Preparations and properties</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU1v1DAQhiMEKkvhxBnJBwQHlOKPJM4et4UuEUVEUKTeokkySb1k7WA7hf51Tng3q4UDp5nR-8x3FD1n9IxRzt5utpTSLAVKxYNowVJO4ySnycNoQSnnMc-4eBw9cW4TMMG4OIlO8pSlCaeL6HdpPGpPlCZ3yltDQLdzcGeCvVW18sY6YjoyDuBxQE-g7y324JXRpAaHLZnG4PpbJCvbx-vhPl65MS5D7PDHhLrBXX6naqu06VGfkRUZrRmNg4EcMjX4ye65XVQr3Srdhwk8WmjmVuh_Iv7t00-gVaD2SV_W727IVm3Rq8btl9hhx5HXJSmKOi6KAojFBsew1NPoUQeDw2cHexp9u3x_ffEhvvq8Li5WVzEkydLHMmcgl5QnggkBAuskT7lM23QJEgFpTVspeS4gCJLVTUI5QpbRrKFStt1SnEav5rph5XAN56utcg0OA2g0k6tkKnPBJA_gmxlsrHHOYleNVm3B3leMVrtPV_98OtAvDmWneovtkT28NugvDzq4BobOgm6UO2JJzihLs4DFM6acx19HGez3KpNCptV1-bU6L2_K9OPyU3UZ-NczD42rNmayOtzuvwP-AYBOzq0</recordid><startdate>199306</startdate><enddate>199306</enddate><creator>Zablocki, Jeffery A</creator><creator>Miyano, Masateru</creator><creator>Garland, Robert B</creator><creator>Pireh, Daisy</creator><creator>Schretzman, Lori</creator><creator>Rao, Shashidhar N</creator><creator>Lindmark, Richard J</creator><creator>Panzer-Knodle, Susan G</creator><creator>Nicholson, Nancy S</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>199306</creationdate><title>Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor</title><author>Zablocki, Jeffery A ; Miyano, Masateru ; Garland, Robert B ; Pireh, Daisy ; Schretzman, Lori ; Rao, Shashidhar N ; Lindmark, Richard J ; Panzer-Knodle, Susan G ; Nicholson, Nancy S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-781a790243133a3eb485275d59a7eae0b0d77283ab4871bc402ea6606c077df93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Benzamidines - chemical synthesis</topic><topic>Benzamidines - metabolism</topic><topic>Benzamidines - pharmacology</topic><topic>Chemistry</topic><topic>Dogs</topic><topic>Exact sciences and technology</topic><topic>Fibrinogen - chemistry</topic><topic>Fibrinogen - metabolism</topic><topic>Guanidine</topic><topic>Guanidines - metabolism</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Models, Chemical</topic><topic>Molecular Sequence Data</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - metabolism</topic><topic>Oligopeptides - pharmacology</topic><topic>Organic chemistry</topic><topic>Peptides</topic><topic>Platelet Aggregation Inhibitors - chemical synthesis</topic><topic>Platelet Aggregation Inhibitors - metabolism</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Platelet Membrane Glycoproteins - metabolism</topic><topic>Preparations and properties</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zablocki, Jeffery A</creatorcontrib><creatorcontrib>Miyano, Masateru</creatorcontrib><creatorcontrib>Garland, Robert B</creatorcontrib><creatorcontrib>Pireh, Daisy</creatorcontrib><creatorcontrib>Schretzman, Lori</creatorcontrib><creatorcontrib>Rao, Shashidhar N</creatorcontrib><creatorcontrib>Lindmark, Richard J</creatorcontrib><creatorcontrib>Panzer-Knodle, Susan G</creatorcontrib><creatorcontrib>Nicholson, Nancy S</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>Zablocki, Jeffery A</au><au>Miyano, Masateru</au><au>Garland, Robert B</au><au>Pireh, Daisy</au><au>Schretzman, Lori</au><au>Rao, Shashidhar N</au><au>Lindmark, Richard J</au><au>Panzer-Knodle, Susan G</au><au>Nicholson, Nancy S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1993-06</date><risdate>1993</risdate><volume>36</volume><issue>13</issue><spage>1811</spage><epage>1819</epage><pages>1811-1819</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Peptide mimetics of the RGDF sequence in which Arg-Gly has been replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carboxylate of the receptor which could explain the dramatic increase in potency upon replacement with benzamidine. This hypothesis is supported by the observation of low inhibitory potency of the corresponding benzylamine (18) and no activity with the corresponding imidazoline derivative (19); plus, ab initio calculations on the respective complexes suggest that the benzamidine-carboxylate is more favorable than the guanidine-carboxylate interaction. The ED50 for the inhibition of ex vivo collagen induced platelet aggregation in the dog for SC-52012 (1) was 0.32 microgram/kg/min by iv infusion with a pharmacodynamic half-life for recovery of approximately 40 min.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8515420</pmid><doi>10.1021/jm00065a003</doi><tpages>9</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1993-06, Vol.36 (13), p.1811-1819 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Amino Acid Sequence Animals Benzamidines - chemical synthesis Benzamidines - metabolism Benzamidines - pharmacology Chemistry Dogs Exact sciences and technology Fibrinogen - chemistry Fibrinogen - metabolism Guanidine Guanidines - metabolism Humans In Vitro Techniques Models, Chemical Molecular Sequence Data Oligopeptides - chemical synthesis Oligopeptides - metabolism Oligopeptides - pharmacology Organic chemistry Peptides Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - metabolism Platelet Aggregation Inhibitors - pharmacology Platelet Membrane Glycoproteins - metabolism Preparations and properties Structure-Activity Relationship |
| title | Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor |
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