Galactosyl Prodrug of Ketorolac: Synthesis, Stability, and Pharmacological and Pharmacokinetic Evaluations
Although ketorolac is one of the most potent anti-inflammatory and analgesic drugs, its use has been strongly limited owing to the high incidence of adverse effects reported, particularly in the gastrointestinal tract. Using the prodrug approach, which allows the reduction of toxicological features...
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-06, Vol.52 (12), p.3794-3800 |
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| container_title | Journal of medicinal chemistry |
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| creator | Curcio, Annalisa Sasso, Oscar Melisi, Daniela Nieddu, Maria La Rana, Giovanna Russo, Roberto Gavini, Elisabetta Boatto, Gianpiero Abignente, Enrico Calignano, Antonio Rimoli, Maria Grazia |
| description | Although ketorolac is one of the most potent anti-inflammatory and analgesic drugs, its use has been strongly limited owing to the high incidence of adverse effects reported, particularly in the gastrointestinal tract. Using the prodrug approach, which allows the reduction of toxicological features of the parent drug without altering its pharmacological properties, we synthesized an orally administrable prodrug of ketorolac by means of its reversible conjugation to d-galactose (ketogal). In a single dose study, its pharmacokinetic profile was compared with that of ketorolac. Moreover, we found that this prodrug was able to maintain the anti-inflammatory and the analgesic activity of the drug without giving rise to gastric ulcer formation. Thus, these results indicate that ketogal is a highly effective and valid therapeutic alternative to ketorolac itself. |
| doi_str_mv | 10.1021/jm900051r |
| format | Article |
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Using the prodrug approach, which allows the reduction of toxicological features of the parent drug without altering its pharmacological properties, we synthesized an orally administrable prodrug of ketorolac by means of its reversible conjugation to d-galactose (ketogal). In a single dose study, its pharmacokinetic profile was compared with that of ketorolac. Moreover, we found that this prodrug was able to maintain the anti-inflammatory and the analgesic activity of the drug without giving rise to gastric ulcer formation. Thus, these results indicate that ketogal is a highly effective and valid therapeutic alternative to ketorolac itself.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm900051r</identifier><identifier>PMID: 19459639</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Analgesics ; Analgesics - chemical synthesis ; Analgesics - chemistry ; Analgesics - pharmacokinetics ; Analgesics - pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Dose-Response Relationship, Drug ; Edema - chemically induced ; Galactose - chemistry ; Hydrogen-Ion Concentration ; Ketorolac - adverse effects ; Ketorolac - chemistry ; Ketorolac - pharmacokinetics ; Ketorolac - pharmacology ; Medical sciences ; Mice ; Molecular Conformation ; Neuropharmacology ; Pain - chemically induced ; Pharmacology. Drug treatments ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacokinetics ; Prodrugs - pharmacology ; Stomach Ulcer - chemically induced ; Time Factors</subject><ispartof>Journal of medicinal chemistry, 2009-06, Vol.52 (12), p.3794-3800</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a343t-dd6e9c286e196e9fff24449715fee2c609c5149b63950110d6ec370a81fbf6603</citedby><cites>FETCH-LOGICAL-a343t-dd6e9c286e196e9fff24449715fee2c609c5149b63950110d6ec370a81fbf6603</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/jm900051r$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm900051r$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21661034$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19459639$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Curcio, Annalisa</creatorcontrib><creatorcontrib>Sasso, Oscar</creatorcontrib><creatorcontrib>Melisi, Daniela</creatorcontrib><creatorcontrib>Nieddu, Maria</creatorcontrib><creatorcontrib>La Rana, Giovanna</creatorcontrib><creatorcontrib>Russo, Roberto</creatorcontrib><creatorcontrib>Gavini, Elisabetta</creatorcontrib><creatorcontrib>Boatto, Gianpiero</creatorcontrib><creatorcontrib>Abignente, Enrico</creatorcontrib><creatorcontrib>Calignano, Antonio</creatorcontrib><creatorcontrib>Rimoli, Maria Grazia</creatorcontrib><title>Galactosyl Prodrug of Ketorolac: Synthesis, Stability, and Pharmacological and Pharmacokinetic Evaluations</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Although ketorolac is one of the most potent anti-inflammatory and analgesic drugs, its use has been strongly limited owing to the high incidence of adverse effects reported, particularly in the gastrointestinal tract. Using the prodrug approach, which allows the reduction of toxicological features of the parent drug without altering its pharmacological properties, we synthesized an orally administrable prodrug of ketorolac by means of its reversible conjugation to d-galactose (ketogal). In a single dose study, its pharmacokinetic profile was compared with that of ketorolac. Moreover, we found that this prodrug was able to maintain the anti-inflammatory and the analgesic activity of the drug without giving rise to gastric ulcer formation. Thus, these results indicate that ketogal is a highly effective and valid therapeutic alternative to ketorolac itself.</description><subject>Analgesics</subject><subject>Analgesics - chemical synthesis</subject><subject>Analgesics - chemistry</subject><subject>Analgesics - pharmacokinetics</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemistry</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Dose-Response Relationship, Drug</subject><subject>Edema - chemically induced</subject><subject>Galactose - chemistry</subject><subject>Hydrogen-Ion Concentration</subject><subject>Ketorolac - adverse effects</subject><subject>Ketorolac - chemistry</subject><subject>Ketorolac - pharmacokinetics</subject><subject>Ketorolac - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Molecular Conformation</subject><subject>Neuropharmacology</subject><subject>Pain - chemically induced</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - pharmacology</subject><subject>Stomach Ulcer - chemically induced</subject><subject>Time Factors</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>eNpt0E1LwzAYB_AgipvTg19AevEgrJq3Zos3GXOKAwfTc0nTZEttG0lSod_eyMZE8JSQ_Hhe_gBcIniLIEZ3VcMhhBlyR2CIMgxTOoX0GAwhxDjFDJMBOPO-ioYgTE7BAHGacUb4EFQLUQsZrO_rZOVs6bpNYnXyooJ1Nv7cJ-u-DVvljR8n6yAKU5vQjxPRlslqK1wjpK3txkhR_3n7MK0KRibzL1F3Ihjb-nNwokXt1cX-HIH3x_nb7Cldvi6eZw_LVBBKQlqWTHGJp0whHm9aa0wp5ROUaaWwZJDLDFFexPEziBCMXJIJFFOkC80YJCNws6srnfXeKZ1_OtMI1-cI5j955Ye8or3a2c-uaFT5K_cBRXC9B8LHHbUTrTT-4DBiDME498EJ6fPKdq6NK_7T8BvI53-G</recordid><startdate>20090625</startdate><enddate>20090625</enddate><creator>Curcio, Annalisa</creator><creator>Sasso, Oscar</creator><creator>Melisi, Daniela</creator><creator>Nieddu, Maria</creator><creator>La Rana, Giovanna</creator><creator>Russo, Roberto</creator><creator>Gavini, Elisabetta</creator><creator>Boatto, Gianpiero</creator><creator>Abignente, Enrico</creator><creator>Calignano, Antonio</creator><creator>Rimoli, Maria Grazia</creator><general>American Chemical Society</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></search><sort><creationdate>20090625</creationdate><title>Galactosyl Prodrug of Ketorolac: Synthesis, Stability, and Pharmacological and Pharmacokinetic Evaluations</title><author>Curcio, Annalisa ; Sasso, Oscar ; Melisi, Daniela ; Nieddu, Maria ; La Rana, Giovanna ; Russo, Roberto ; Gavini, Elisabetta ; Boatto, Gianpiero ; Abignente, Enrico ; Calignano, Antonio ; Rimoli, Maria Grazia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a343t-dd6e9c286e196e9fff24449715fee2c609c5149b63950110d6ec370a81fbf6603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Analgesics</topic><topic>Analgesics - chemical synthesis</topic><topic>Analgesics - chemistry</topic><topic>Analgesics - pharmacokinetics</topic><topic>Analgesics - pharmacology</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemistry</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Dose-Response Relationship, Drug</topic><topic>Edema - chemically induced</topic><topic>Galactose - chemistry</topic><topic>Hydrogen-Ion Concentration</topic><topic>Ketorolac - adverse effects</topic><topic>Ketorolac - chemistry</topic><topic>Ketorolac - pharmacokinetics</topic><topic>Ketorolac - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Molecular Conformation</topic><topic>Neuropharmacology</topic><topic>Pain - chemically induced</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacokinetics</topic><topic>Prodrugs - pharmacology</topic><topic>Stomach Ulcer - chemically induced</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Curcio, Annalisa</creatorcontrib><creatorcontrib>Sasso, Oscar</creatorcontrib><creatorcontrib>Melisi, Daniela</creatorcontrib><creatorcontrib>Nieddu, Maria</creatorcontrib><creatorcontrib>La Rana, Giovanna</creatorcontrib><creatorcontrib>Russo, Roberto</creatorcontrib><creatorcontrib>Gavini, Elisabetta</creatorcontrib><creatorcontrib>Boatto, Gianpiero</creatorcontrib><creatorcontrib>Abignente, Enrico</creatorcontrib><creatorcontrib>Calignano, Antonio</creatorcontrib><creatorcontrib>Rimoli, Maria Grazia</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Curcio, Annalisa</au><au>Sasso, Oscar</au><au>Melisi, Daniela</au><au>Nieddu, Maria</au><au>La Rana, Giovanna</au><au>Russo, Roberto</au><au>Gavini, Elisabetta</au><au>Boatto, Gianpiero</au><au>Abignente, Enrico</au><au>Calignano, Antonio</au><au>Rimoli, Maria Grazia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Galactosyl Prodrug of Ketorolac: Synthesis, Stability, and Pharmacological and Pharmacokinetic Evaluations</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-06-25</date><risdate>2009</risdate><volume>52</volume><issue>12</issue><spage>3794</spage><epage>3800</epage><pages>3794-3800</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Although ketorolac is one of the most potent anti-inflammatory and analgesic drugs, its use has been strongly limited owing to the high incidence of adverse effects reported, particularly in the gastrointestinal tract. Using the prodrug approach, which allows the reduction of toxicological features of the parent drug without altering its pharmacological properties, we synthesized an orally administrable prodrug of ketorolac by means of its reversible conjugation to d-galactose (ketogal). In a single dose study, its pharmacokinetic profile was compared with that of ketorolac. Moreover, we found that this prodrug was able to maintain the anti-inflammatory and the analgesic activity of the drug without giving rise to gastric ulcer formation. Thus, these results indicate that ketogal is a highly effective and valid therapeutic alternative to ketorolac itself.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19459639</pmid><doi>10.1021/jm900051r</doi><tpages>7</tpages></addata></record> |
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| source | MEDLINE; ACS Publications |
| subjects | Analgesics Analgesics - chemical synthesis Analgesics - chemistry Analgesics - pharmacokinetics Analgesics - pharmacology Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Anti-Inflammatory Agents, Non-Steroidal - pharmacology Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Dose-Response Relationship, Drug Edema - chemically induced Galactose - chemistry Hydrogen-Ion Concentration Ketorolac - adverse effects Ketorolac - chemistry Ketorolac - pharmacokinetics Ketorolac - pharmacology Medical sciences Mice Molecular Conformation Neuropharmacology Pain - chemically induced Pharmacology. Drug treatments Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacokinetics Prodrugs - pharmacology Stomach Ulcer - chemically induced Time Factors |
| title | Galactosyl Prodrug of Ketorolac: Synthesis, Stability, and Pharmacological and Pharmacokinetic Evaluations |
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