1,2-Disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors
A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor. Two...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 1998-05, Vol.8 (10), p.1249-1254 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Harmat, Nicholas J.S. Di Bugno, Cristina Criscuoli, M. Giorgi, Raffaello Lippi, Annalisa Martinelli, Adriano Monti, Susanna Subissi, A. |
| description | A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor.
Two series of tripeptide arginine aldehydes Ph(CH
2)
nNH(Me)-1,2-COcC
6H
10COArgH and D-MePhe-1,2-(CONH)cC
6H
10COArgH bearing a central 1,2-disubstituted cyclohexane moiety of defined stereochemistry were synthesized and screened for thrombin inhibition activity. Later modification of the aromatic side chain in the light of modeling studies led to the potent and selective inhibitor
13e. |
| doi_str_mv | 10.1016/S0960-894X(98)00200-5 |
| format | Article |
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Two series of tripeptide arginine aldehydes Ph(CH
2)
nNH(Me)-1,2-COcC
6H
10COArgH and D-MePhe-1,2-(CONH)cC
6H
10COArgH bearing a central 1,2-disubstituted cyclohexane moiety of defined stereochemistry were synthesized and screened for thrombin inhibition activity. Later modification of the aromatic side chain in the light of modeling studies led to the potent and selective inhibitor
13e.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/S0960-894X(98)00200-5</identifier><identifier>PMID: 9871744</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Aldehydes ; Amino Acid Sequence ; Antithrombins - chemical synthesis ; Antithrombins - chemistry ; Antithrombins - pharmacology ; Arginine ; Binding Sites ; Biological and medical sciences ; Blood. Blood coagulation. Reticuloendothelial system ; Cyclohexanes - chemical synthesis ; Cyclohexanes - chemistry ; Cyclohexanes - pharmacology ; Indicators and Reagents ; Kinetics ; Medical sciences ; Models, Molecular ; Molecular Structure ; Oligopeptides - chemical synthesis ; Oligopeptides - chemistry ; Oligopeptides - pharmacology ; Pharmacology. Drug treatments ; Protein Conformation ; Stereoisomerism ; Structure-Activity Relationship ; Thrombin - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 1998-05, Vol.8 (10), p.1249-1254</ispartof><rights>1998</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-2d937b604e435349b847b48a5bf6080e25d8bf09cc57f1e940b780a2ec63b98e3</citedby><cites>FETCH-LOGICAL-c389t-2d937b604e435349b847b48a5bf6080e25d8bf09cc57f1e940b780a2ec63b98e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0960-894X(98)00200-5$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2248271$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9871744$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Harmat, Nicholas J.S.</creatorcontrib><creatorcontrib>Di Bugno, Cristina</creatorcontrib><creatorcontrib>Criscuoli, M.</creatorcontrib><creatorcontrib>Giorgi, Raffaello</creatorcontrib><creatorcontrib>Lippi, Annalisa</creatorcontrib><creatorcontrib>Martinelli, Adriano</creatorcontrib><creatorcontrib>Monti, Susanna</creatorcontrib><creatorcontrib>Subissi, A.</creatorcontrib><title>1,2-Disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor.
Two series of tripeptide arginine aldehydes Ph(CH
2)
nNH(Me)-1,2-COcC
6H
10COArgH and D-MePhe-1,2-(CONH)cC
6H
10COArgH bearing a central 1,2-disubstituted cyclohexane moiety of defined stereochemistry were synthesized and screened for thrombin inhibition activity. Later modification of the aromatic side chain in the light of modeling studies led to the potent and selective inhibitor
13e.</description><subject>Aldehydes</subject><subject>Amino Acid Sequence</subject><subject>Antithrombins - chemical synthesis</subject><subject>Antithrombins - chemistry</subject><subject>Antithrombins - pharmacology</subject><subject>Arginine</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Cyclohexanes - chemical synthesis</subject><subject>Cyclohexanes - chemistry</subject><subject>Cyclohexanes - pharmacology</subject><subject>Indicators and Reagents</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Conformation</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Thrombin - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtrFEEQgBtR4ib6EwJzEIngxOqenpnuk0iMGgh4UMFb048atmV2Zu3qWbL_3k522aungqqvXh9jlxyuOfDuww_QHdRKy99XWr0DEAB1-4ytuOxk3Uhon7PVCXnJzon-AHAJUp6xM6163ku5Ypa_F_XnSIujHPOSMVR-78d5jQ92wipgiruSyylucZtjwMqOAdf7gFRZqqZ5h2NFOKLPBazyOs0bF6cqTuvoYp4TvWIvBjsSvj7GC_bry-3Pm2_1_fevdzef7mvfKJ1rEXTTuw4kyqZtpHZK9k4q27qhAwUo2qDcANr7th84agmuV2AF-q5xWmFzwd4e5m7T_HdBymYTyeM4lj_mhUynORdKQAHbA-jTTJRwMNsUNzbtDQfzqNY8qTWP3oxW5kmtaUvf5XHB4jYYTl1Hl6X-5li35O04JDv5SCdMCKlEzwv28YBhkbGLmAz5iJPHEFOxaMIc_3PIP8HUlvo</recordid><startdate>19980519</startdate><enddate>19980519</enddate><creator>Harmat, Nicholas J.S.</creator><creator>Di Bugno, Cristina</creator><creator>Criscuoli, M.</creator><creator>Giorgi, Raffaello</creator><creator>Lippi, Annalisa</creator><creator>Martinelli, Adriano</creator><creator>Monti, Susanna</creator><creator>Subissi, A.</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>19980519</creationdate><title>1,2-Disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors</title><author>Harmat, Nicholas J.S. ; Di Bugno, Cristina ; Criscuoli, M. ; Giorgi, Raffaello ; Lippi, Annalisa ; Martinelli, Adriano ; Monti, Susanna ; Subissi, A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-2d937b604e435349b847b48a5bf6080e25d8bf09cc57f1e940b780a2ec63b98e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Aldehydes</topic><topic>Amino Acid Sequence</topic><topic>Antithrombins - chemical synthesis</topic><topic>Antithrombins - chemistry</topic><topic>Antithrombins - pharmacology</topic><topic>Arginine</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Cyclohexanes - chemical synthesis</topic><topic>Cyclohexanes - chemistry</topic><topic>Cyclohexanes - pharmacology</topic><topic>Indicators and Reagents</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Conformation</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Thrombin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Harmat, Nicholas J.S.</creatorcontrib><creatorcontrib>Di Bugno, Cristina</creatorcontrib><creatorcontrib>Criscuoli, M.</creatorcontrib><creatorcontrib>Giorgi, Raffaello</creatorcontrib><creatorcontrib>Lippi, Annalisa</creatorcontrib><creatorcontrib>Martinelli, Adriano</creatorcontrib><creatorcontrib>Monti, Susanna</creatorcontrib><creatorcontrib>Subissi, A.</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>Harmat, Nicholas J.S.</au><au>Di Bugno, Cristina</au><au>Criscuoli, M.</au><au>Giorgi, Raffaello</au><au>Lippi, Annalisa</au><au>Martinelli, Adriano</au><au>Monti, Susanna</au><au>Subissi, A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1,2-Disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>1998-05-19</date><risdate>1998</risdate><volume>8</volume><issue>10</issue><spage>1249</spage><epage>1254</epage><pages>1249-1254</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor.
Two series of tripeptide arginine aldehydes Ph(CH
2)
nNH(Me)-1,2-COcC
6H
10COArgH and D-MePhe-1,2-(CONH)cC
6H
10COArgH bearing a central 1,2-disubstituted cyclohexane moiety of defined stereochemistry were synthesized and screened for thrombin inhibition activity. Later modification of the aromatic side chain in the light of modeling studies led to the potent and selective inhibitor
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| ispartof | Bioorganic & medicinal chemistry letters, 1998-05, Vol.8 (10), p.1249-1254 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Aldehydes Amino Acid Sequence Antithrombins - chemical synthesis Antithrombins - chemistry Antithrombins - pharmacology Arginine Binding Sites Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Cyclohexanes - chemical synthesis Cyclohexanes - chemistry Cyclohexanes - pharmacology Indicators and Reagents Kinetics Medical sciences Models, Molecular Molecular Structure Oligopeptides - chemical synthesis Oligopeptides - chemistry Oligopeptides - pharmacology Pharmacology. Drug treatments Protein Conformation Stereoisomerism Structure-Activity Relationship Thrombin - metabolism |
| title | 1,2-Disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors |
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