Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor
We have optimized 1 (P5U) and urantide, two important ligands at the h-UT receptor, designing several analogues by the exchange of the Tyr9 residue with different unnatural aromatic amino acids. This study allowed us to discover novel ligands with improved activity. In particular, the replacement of...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2014-07, Vol.57 (14), p.5965-5974 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 5974 |
|---|---|
| container_issue | 14 |
| container_start_page | 5965 |
| container_title | Journal of medicinal chemistry |
| container_volume | 57 |
| creator | Carotenuto, Alfonso Auriemma, Luigia Merlino, Francesco Yousif, Ali Munaim Marasco, Daniela Limatola, Antonio Campiglia, Pietro Gomez-Monterrey, Isabel Santicioli, Paolo Meini, Stefania Maggi, Carlo A Novellino, Ettore Grieco, Paolo |
| description | We have optimized 1 (P5U) and urantide, two important ligands at the h-UT receptor, designing several analogues by the exchange of the Tyr9 residue with different unnatural aromatic amino acids. This study allowed us to discover novel ligands with improved activity. In particular, the replacement of the Tyr9 residue by (pCN)Phe or (pNO2)Phe within the urantide sequence led to compounds 13 (UPG-83) and 15 (UPG-95), respectively, which showed pure antagonist activity toward UT receptor in a rat aorta bioassay. More interestingly, the replacement of the Tyr9 in 1 sequence with the Btz or the (3,4-Cl)Phe residues led to superagonists 6 (UPG-100) and 10 (UPG-92) with pEC50 values at least 1.4 log higher than that of 1, being the most potent UT agonists discovered to date. Compounds 10 and 13 showed also a good stability in a serum proteolytic assay. These ligands represent new useful tools to further characterize the urotensinergic system in human physiopathology. |
| doi_str_mv | 10.1021/jm500218x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1548635962</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1548635962</sourcerecordid><originalsourceid>FETCH-LOGICAL-a315t-9c97b85e3f16e8e15e1afe7ff09ee2842014cf67a027d1df16a7d187dac63cbf3</originalsourceid><addsrcrecordid>eNptkMtOwzAQRS0EoqWw4AeQN0iwCPgR58EOlVeliFaIriM3GYOrJg62gyhfj6tCV6zuaObM1cxF6JSSK0oYvV42ggTNvvbQkApGojgj8T4ahiaLWML4AB05tySEcMr4IRqwOM8ZT-MhggJkjaed143-ll6bFhuFZ2KOZVvjuZWt1zXc4DvtKvMJdr0ZP4dqhWfGQ-txod8C6rD02L9DWNm0nW6jyQS_QAWdN_YYHSi5cnDyqyM0f7h_HT9FxfRxMr4tIsmp8FFe5ekiE8AVTSADKoBKBalSJAdgWcwIjSuVpJKwtKZ1oGTQLK1llfBqofgIXWx9O2s-enC-bMLdsFrJFkzvSiriLOEiD5GM0OUWraxxzoIqO6sbadclJeUm1XKXamDPfm37RQP1jvyLMQDnW0BWrlya3rbhy3-MfgBYJH4u</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1548635962</pqid></control><display><type>article</type><title>Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor</title><source>MEDLINE</source><source>ACS Publications</source><creator>Carotenuto, Alfonso ; Auriemma, Luigia ; Merlino, Francesco ; Yousif, Ali Munaim ; Marasco, Daniela ; Limatola, Antonio ; Campiglia, Pietro ; Gomez-Monterrey, Isabel ; Santicioli, Paolo ; Meini, Stefania ; Maggi, Carlo A ; Novellino, Ettore ; Grieco, Paolo</creator><creatorcontrib>Carotenuto, Alfonso ; Auriemma, Luigia ; Merlino, Francesco ; Yousif, Ali Munaim ; Marasco, Daniela ; Limatola, Antonio ; Campiglia, Pietro ; Gomez-Monterrey, Isabel ; Santicioli, Paolo ; Meini, Stefania ; Maggi, Carlo A ; Novellino, Ettore ; Grieco, Paolo</creatorcontrib><description>We have optimized 1 (P5U) and urantide, two important ligands at the h-UT receptor, designing several analogues by the exchange of the Tyr9 residue with different unnatural aromatic amino acids. This study allowed us to discover novel ligands with improved activity. In particular, the replacement of the Tyr9 residue by (pCN)Phe or (pNO2)Phe within the urantide sequence led to compounds 13 (UPG-83) and 15 (UPG-95), respectively, which showed pure antagonist activity toward UT receptor in a rat aorta bioassay. More interestingly, the replacement of the Tyr9 in 1 sequence with the Btz or the (3,4-Cl)Phe residues led to superagonists 6 (UPG-100) and 10 (UPG-92) with pEC50 values at least 1.4 log higher than that of 1, being the most potent UT agonists discovered to date. Compounds 10 and 13 showed also a good stability in a serum proteolytic assay. These ligands represent new useful tools to further characterize the urotensinergic system in human physiopathology.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm500218x</identifier><identifier>PMID: 24992374</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Dose-Response Relationship, Drug ; Drug Discovery ; Humans ; Ligands ; Models, Molecular ; Molecular Conformation ; Peptide Fragments - chemical synthesis ; Peptide Fragments - chemistry ; Peptide Fragments - pharmacology ; Peptides, Cyclic - chemical synthesis ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - pharmacology ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Receptors, G-Protein-Coupled - metabolism ; Structure-Activity Relationship ; Urotensins - chemical synthesis ; Urotensins - chemistry ; Urotensins - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2014-07, Vol.57 (14), p.5965-5974</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-9c97b85e3f16e8e15e1afe7ff09ee2842014cf67a027d1df16a7d187dac63cbf3</citedby><cites>FETCH-LOGICAL-a315t-9c97b85e3f16e8e15e1afe7ff09ee2842014cf67a027d1df16a7d187dac63cbf3</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/jm500218x$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm500218x$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24992374$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carotenuto, Alfonso</creatorcontrib><creatorcontrib>Auriemma, Luigia</creatorcontrib><creatorcontrib>Merlino, Francesco</creatorcontrib><creatorcontrib>Yousif, Ali Munaim</creatorcontrib><creatorcontrib>Marasco, Daniela</creatorcontrib><creatorcontrib>Limatola, Antonio</creatorcontrib><creatorcontrib>Campiglia, Pietro</creatorcontrib><creatorcontrib>Gomez-Monterrey, Isabel</creatorcontrib><creatorcontrib>Santicioli, Paolo</creatorcontrib><creatorcontrib>Meini, Stefania</creatorcontrib><creatorcontrib>Maggi, Carlo A</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Grieco, Paolo</creatorcontrib><title>Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We have optimized 1 (P5U) and urantide, two important ligands at the h-UT receptor, designing several analogues by the exchange of the Tyr9 residue with different unnatural aromatic amino acids. This study allowed us to discover novel ligands with improved activity. In particular, the replacement of the Tyr9 residue by (pCN)Phe or (pNO2)Phe within the urantide sequence led to compounds 13 (UPG-83) and 15 (UPG-95), respectively, which showed pure antagonist activity toward UT receptor in a rat aorta bioassay. More interestingly, the replacement of the Tyr9 in 1 sequence with the Btz or the (3,4-Cl)Phe residues led to superagonists 6 (UPG-100) and 10 (UPG-92) with pEC50 values at least 1.4 log higher than that of 1, being the most potent UT agonists discovered to date. Compounds 10 and 13 showed also a good stability in a serum proteolytic assay. These ligands represent new useful tools to further characterize the urotensinergic system in human physiopathology.</description><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Humans</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Peptide Fragments - chemical synthesis</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - pharmacology</subject><subject>Peptides, Cyclic - chemical synthesis</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Urotensins - chemical synthesis</subject><subject>Urotensins - chemistry</subject><subject>Urotensins - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtOwzAQRS0EoqWw4AeQN0iwCPgR58EOlVeliFaIriM3GYOrJg62gyhfj6tCV6zuaObM1cxF6JSSK0oYvV42ggTNvvbQkApGojgj8T4ahiaLWML4AB05tySEcMr4IRqwOM8ZT-MhggJkjaed143-ll6bFhuFZ2KOZVvjuZWt1zXc4DvtKvMJdr0ZP4dqhWfGQ-txod8C6rD02L9DWNm0nW6jyQS_QAWdN_YYHSi5cnDyqyM0f7h_HT9FxfRxMr4tIsmp8FFe5ekiE8AVTSADKoBKBalSJAdgWcwIjSuVpJKwtKZ1oGTQLK1llfBqofgIXWx9O2s-enC-bMLdsFrJFkzvSiriLOEiD5GM0OUWraxxzoIqO6sbadclJeUm1XKXamDPfm37RQP1jvyLMQDnW0BWrlya3rbhy3-MfgBYJH4u</recordid><startdate>20140724</startdate><enddate>20140724</enddate><creator>Carotenuto, Alfonso</creator><creator>Auriemma, Luigia</creator><creator>Merlino, Francesco</creator><creator>Yousif, Ali Munaim</creator><creator>Marasco, Daniela</creator><creator>Limatola, Antonio</creator><creator>Campiglia, Pietro</creator><creator>Gomez-Monterrey, Isabel</creator><creator>Santicioli, Paolo</creator><creator>Meini, Stefania</creator><creator>Maggi, Carlo A</creator><creator>Novellino, Ettore</creator><creator>Grieco, Paolo</creator><general>American Chemical Society</general><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>20140724</creationdate><title>Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor</title><author>Carotenuto, Alfonso ; Auriemma, Luigia ; Merlino, Francesco ; Yousif, Ali Munaim ; Marasco, Daniela ; Limatola, Antonio ; Campiglia, Pietro ; Gomez-Monterrey, Isabel ; Santicioli, Paolo ; Meini, Stefania ; Maggi, Carlo A ; Novellino, Ettore ; Grieco, Paolo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-9c97b85e3f16e8e15e1afe7ff09ee2842014cf67a027d1df16a7d187dac63cbf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Humans</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Peptide Fragments - chemical synthesis</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - pharmacology</topic><topic>Peptides, Cyclic - chemical synthesis</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Receptors, G-Protein-Coupled - antagonists & inhibitors</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Urotensins - chemical synthesis</topic><topic>Urotensins - chemistry</topic><topic>Urotensins - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carotenuto, Alfonso</creatorcontrib><creatorcontrib>Auriemma, Luigia</creatorcontrib><creatorcontrib>Merlino, Francesco</creatorcontrib><creatorcontrib>Yousif, Ali Munaim</creatorcontrib><creatorcontrib>Marasco, Daniela</creatorcontrib><creatorcontrib>Limatola, Antonio</creatorcontrib><creatorcontrib>Campiglia, Pietro</creatorcontrib><creatorcontrib>Gomez-Monterrey, Isabel</creatorcontrib><creatorcontrib>Santicioli, Paolo</creatorcontrib><creatorcontrib>Meini, Stefania</creatorcontrib><creatorcontrib>Maggi, Carlo A</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Grieco, Paolo</creatorcontrib><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>Carotenuto, Alfonso</au><au>Auriemma, Luigia</au><au>Merlino, Francesco</au><au>Yousif, Ali Munaim</au><au>Marasco, Daniela</au><au>Limatola, Antonio</au><au>Campiglia, Pietro</au><au>Gomez-Monterrey, Isabel</au><au>Santicioli, Paolo</au><au>Meini, Stefania</au><au>Maggi, Carlo A</au><au>Novellino, Ettore</au><au>Grieco, Paolo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-07-24</date><risdate>2014</risdate><volume>57</volume><issue>14</issue><spage>5965</spage><epage>5974</epage><pages>5965-5974</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We have optimized 1 (P5U) and urantide, two important ligands at the h-UT receptor, designing several analogues by the exchange of the Tyr9 residue with different unnatural aromatic amino acids. This study allowed us to discover novel ligands with improved activity. In particular, the replacement of the Tyr9 residue by (pCN)Phe or (pNO2)Phe within the urantide sequence led to compounds 13 (UPG-83) and 15 (UPG-95), respectively, which showed pure antagonist activity toward UT receptor in a rat aorta bioassay. More interestingly, the replacement of the Tyr9 in 1 sequence with the Btz or the (3,4-Cl)Phe residues led to superagonists 6 (UPG-100) and 10 (UPG-92) with pEC50 values at least 1.4 log higher than that of 1, being the most potent UT agonists discovered to date. Compounds 10 and 13 showed also a good stability in a serum proteolytic assay. These ligands represent new useful tools to further characterize the urotensinergic system in human physiopathology.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24992374</pmid><doi>10.1021/jm500218x</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2014-07, Vol.57 (14), p.5965-5974 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1548635962 |
| source | MEDLINE; ACS Publications |
| subjects | Dose-Response Relationship, Drug Drug Discovery Humans Ligands Models, Molecular Molecular Conformation Peptide Fragments - chemical synthesis Peptide Fragments - chemistry Peptide Fragments - pharmacology Peptides, Cyclic - chemical synthesis Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - metabolism Structure-Activity Relationship Urotensins - chemical synthesis Urotensins - chemistry Urotensins - pharmacology |
| title | Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T09%3A32%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Lead%20Optimization%20of%20P5U%20and%20Urantide:%20Discovery%20of%20Novel%20Potent%20Ligands%20at%20the%20Urotensin-II%20Receptor&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Carotenuto,%20Alfonso&rft.date=2014-07-24&rft.volume=57&rft.issue=14&rft.spage=5965&rft.epage=5974&rft.pages=5965-5974&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm500218x&rft_dat=%3Cproquest_cross%3E1548635962%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1548635962&rft_id=info:pmid/24992374&rfr_iscdi=true |