Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol- O-methyltransferase inhibitor
Compound 1 is an investigational, nanomolar inhibitor of catechol- O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophili...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (8), p.2614-2616 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2616 |
|---|---|
| container_issue | 8 |
| container_start_page | 2614 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 20 |
| creator | Rautio, Jarkko Leppänen, Jukka Lehtonen, Marko Laine, Krista Koskinen, Mikko Pystynen, Jarmo Savolainen, Jouko Sairanen, Mikko |
| description | Compound
1 is an investigational, nanomolar inhibitor of catechol-
O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of
1 was observed with two prodrugs, compared to that of
1, after oral treatment in rats. |
| doi_str_mv | 10.1016/j.bmcl.2010.02.057 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_746229576</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X1000257X</els_id><sourcerecordid>733852753</sourcerecordid><originalsourceid>FETCH-LOGICAL-c483t-479eee9468d21a47fe41f8a7e6c08387a87693572fec5ef5bae1a989e05825f33</originalsourceid><addsrcrecordid>eNqFkT2P1DAQhiME4paDP0CB3CAasmc7duxINOj4lE66BiQ6a-JMbr3yxoftRNqG347DLtBB5ZHnmVejearqOaNbRll7td_2B-u3nJYPyrdUqgfVholW1I2g8mG1oV1La92JbxfVk5T2lDJBhXhcXXDKG0Y7ual-vMPk7qbXJB2nvCt1IjANxE1kcTmGq1_FEggu4GfILkwkjCRE8P5IehdgAeeh90juYxjifJfWPhALGe0u-Jrc1gfMu6PPEaY0YoSEJX7nepdDfFo9GsEnfHZ-L6uvH95_uf5U39x-_Hz99qa2Qje5FqpDxE60euAMhBpRsFGDwtZS3WgFWrVdIxUf0UocZQ_IoNMdUqm5HJvmsnp1yi1bfp8xZXNwyaL3MGGYk1Gi5byTqv0_2TRaciXXTH4ibQwpRRzNfXQHiEfDqFkFmb1ZBZlVkKHcFEFl6MU5fu4POPwZ-W2kAC_PACQLfixXsy795bjmolOscG9OHJazLQ6jSdbhZHFwEW02Q3D_2uMnlSawRA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>733852753</pqid></control><display><type>article</type><title>Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol- O-methyltransferase inhibitor</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Rautio, Jarkko ; Leppänen, Jukka ; Lehtonen, Marko ; Laine, Krista ; Koskinen, Mikko ; Pystynen, Jarmo ; Savolainen, Jouko ; Sairanen, Mikko</creator><creatorcontrib>Rautio, Jarkko ; Leppänen, Jukka ; Lehtonen, Marko ; Laine, Krista ; Koskinen, Mikko ; Pystynen, Jarmo ; Savolainen, Jouko ; Sairanen, Mikko</creatorcontrib><description>Compound
1 is an investigational, nanomolar inhibitor of catechol-
O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of
1 was observed with two prodrugs, compared to that of
1, after oral treatment in rats.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.02.057</identifier><identifier>PMID: 20231095</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; Animals ; Anticonvulsants. Antiepileptics. Antiparkinson agents ; Biological and medical sciences ; Biological Availability ; Catechol O-Methyltransferase Inhibitors ; COMT inhibitor ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Humans ; Male ; Medical sciences ; Neuropharmacology ; Oral bioavailability ; Pharmacology. Drug treatments ; Prodrug ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacokinetics ; Prodrugs - pharmacology ; Rats ; Rats, Wistar</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-04, Vol.20 (8), p.2614-2616</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-479eee9468d21a47fe41f8a7e6c08387a87693572fec5ef5bae1a989e05825f33</citedby><cites>FETCH-LOGICAL-c483t-479eee9468d21a47fe41f8a7e6c08387a87693572fec5ef5bae1a989e05825f33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X1000257X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22824971$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20231095$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rautio, Jarkko</creatorcontrib><creatorcontrib>Leppänen, Jukka</creatorcontrib><creatorcontrib>Lehtonen, Marko</creatorcontrib><creatorcontrib>Laine, Krista</creatorcontrib><creatorcontrib>Koskinen, Mikko</creatorcontrib><creatorcontrib>Pystynen, Jarmo</creatorcontrib><creatorcontrib>Savolainen, Jouko</creatorcontrib><creatorcontrib>Sairanen, Mikko</creatorcontrib><title>Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol- O-methyltransferase inhibitor</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Compound
1 is an investigational, nanomolar inhibitor of catechol-
O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of
1 was observed with two prodrugs, compared to that of
1, after oral treatment in rats.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Anticonvulsants. Antiepileptics. Antiparkinson agents</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Catechol O-Methyltransferase Inhibitors</subject><subject>COMT inhibitor</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Oral bioavailability</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrug</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkT2P1DAQhiME4paDP0CB3CAasmc7duxINOj4lE66BiQ6a-JMbr3yxoftRNqG347DLtBB5ZHnmVejearqOaNbRll7td_2B-u3nJYPyrdUqgfVholW1I2g8mG1oV1La92JbxfVk5T2lDJBhXhcXXDKG0Y7ual-vMPk7qbXJB2nvCt1IjANxE1kcTmGq1_FEggu4GfILkwkjCRE8P5IehdgAeeh90juYxjifJfWPhALGe0u-Jrc1gfMu6PPEaY0YoSEJX7nepdDfFo9GsEnfHZ-L6uvH95_uf5U39x-_Hz99qa2Qje5FqpDxE60euAMhBpRsFGDwtZS3WgFWrVdIxUf0UocZQ_IoNMdUqm5HJvmsnp1yi1bfp8xZXNwyaL3MGGYk1Gi5byTqv0_2TRaciXXTH4ibQwpRRzNfXQHiEfDqFkFmb1ZBZlVkKHcFEFl6MU5fu4POPwZ-W2kAC_PACQLfixXsy795bjmolOscG9OHJazLQ6jSdbhZHFwEW02Q3D_2uMnlSawRA</recordid><startdate>20100415</startdate><enddate>20100415</enddate><creator>Rautio, Jarkko</creator><creator>Leppänen, Jukka</creator><creator>Lehtonen, Marko</creator><creator>Laine, Krista</creator><creator>Koskinen, Mikko</creator><creator>Pystynen, Jarmo</creator><creator>Savolainen, Jouko</creator><creator>Sairanen, Mikko</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20100415</creationdate><title>Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol- O-methyltransferase inhibitor</title><author>Rautio, Jarkko ; Leppänen, Jukka ; Lehtonen, Marko ; Laine, Krista ; Koskinen, Mikko ; Pystynen, Jarmo ; Savolainen, Jouko ; Sairanen, Mikko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-479eee9468d21a47fe41f8a7e6c08387a87693572fec5ef5bae1a989e05825f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Anticonvulsants. Antiepileptics. Antiparkinson agents</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Catechol O-Methyltransferase Inhibitors</topic><topic>COMT inhibitor</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Oral bioavailability</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrug</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacokinetics</topic><topic>Prodrugs - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rautio, Jarkko</creatorcontrib><creatorcontrib>Leppänen, Jukka</creatorcontrib><creatorcontrib>Lehtonen, Marko</creatorcontrib><creatorcontrib>Laine, Krista</creatorcontrib><creatorcontrib>Koskinen, Mikko</creatorcontrib><creatorcontrib>Pystynen, Jarmo</creatorcontrib><creatorcontrib>Savolainen, Jouko</creatorcontrib><creatorcontrib>Sairanen, Mikko</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rautio, Jarkko</au><au>Leppänen, Jukka</au><au>Lehtonen, Marko</au><au>Laine, Krista</au><au>Koskinen, Mikko</au><au>Pystynen, Jarmo</au><au>Savolainen, Jouko</au><au>Sairanen, Mikko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol- O-methyltransferase inhibitor</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-04-15</date><risdate>2010</risdate><volume>20</volume><issue>8</issue><spage>2614</spage><epage>2616</epage><pages>2614-2616</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Compound
1 is an investigational, nanomolar inhibitor of catechol-
O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of
1 was observed with two prodrugs, compared to that of
1, after oral treatment in rats.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20231095</pmid><doi>10.1016/j.bmcl.2010.02.057</doi><tpages>3</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-04, Vol.20 (8), p.2614-2616 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_746229576 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral Animals Anticonvulsants. Antiepileptics. Antiparkinson agents Biological and medical sciences Biological Availability Catechol O-Methyltransferase Inhibitors COMT inhibitor Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Humans Male Medical sciences Neuropharmacology Oral bioavailability Pharmacology. Drug treatments Prodrug Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacokinetics Prodrugs - pharmacology Rats Rats, Wistar |
| title | Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol- O-methyltransferase inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T23%3A54%3A45IST&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=Design,%20synthesis%20and%20in%20vitro/in%20vivo%20evaluation%20of%20orally%20bioavailable%20prodrugs%20of%20a%20catechol-%20O-methyltransferase%20inhibitor&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Rautio,%20Jarkko&rft.date=2010-04-15&rft.volume=20&rft.issue=8&rft.spage=2614&rft.epage=2616&rft.pages=2614-2616&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2010.02.057&rft_dat=%3Cproquest_cross%3E733852753%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=733852753&rft_id=info:pmid/20231095&rft_els_id=S0960894X1000257X&rfr_iscdi=true |