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Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay
[Display omitted] Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors f...
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| Published in: | Bioorganic & medicinal chemistry letters 2015-06, Vol.25 (12), p.2505-2509 |
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| Main Authors: | , , , , , , , , , , , , , |
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| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c356t-dc105913811e6afe1667518a6d7d7b55ee584332db95a0383aa7fbe0f2b25ece3 |
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| cites | cdi_FETCH-LOGICAL-c356t-dc105913811e6afe1667518a6d7d7b55ee584332db95a0383aa7fbe0f2b25ece3 |
| container_end_page | 2509 |
| container_issue | 12 |
| container_start_page | 2505 |
| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Arns, Steve Tan, Jason Sun, Sharon Galey, Adam Zisman, Natalia Ross, Fiona Udechukwu, Jenna Dercho, Samantha Gusti, Vionarica Paquette, Jay Webb, Murray Bourque, Elyse Withers, Stephen G. Liggins, Richard |
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Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs. |
| doi_str_mv | 10.1016/j.bmcl.2015.04.059 |
| format | article |
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Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.04.059</identifier><identifier>PMID: 25980910</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Administration, Oral ; Animals ; Bioavailability ; Biological Availability ; Difluorosialic acid ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacokinetics ; Half-Life ; Mice ; Neuraminidase - antagonists & inhibitors ; Neuraminidase - metabolism ; Neuraminidase inhibitor ; Prodrug ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacokinetics ; Sialic Acids - chemical synthesis ; Sialic Acids - chemistry ; Sialic Acids - pharmacokinetics ; Snapshot PK screen ; Viral Proteins - antagonists & inhibitors ; Viral Proteins - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-06, Vol.25 (12), p.2505-2509</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-dc105913811e6afe1667518a6d7d7b55ee584332db95a0383aa7fbe0f2b25ece3</citedby><cites>FETCH-LOGICAL-c356t-dc105913811e6afe1667518a6d7d7b55ee584332db95a0383aa7fbe0f2b25ece3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25980910$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arns, Steve</creatorcontrib><creatorcontrib>Tan, Jason</creatorcontrib><creatorcontrib>Sun, Sharon</creatorcontrib><creatorcontrib>Galey, Adam</creatorcontrib><creatorcontrib>Zisman, Natalia</creatorcontrib><creatorcontrib>Ross, Fiona</creatorcontrib><creatorcontrib>Udechukwu, Jenna</creatorcontrib><creatorcontrib>Dercho, Samantha</creatorcontrib><creatorcontrib>Gusti, Vionarica</creatorcontrib><creatorcontrib>Paquette, Jay</creatorcontrib><creatorcontrib>Webb, Murray</creatorcontrib><creatorcontrib>Bourque, Elyse</creatorcontrib><creatorcontrib>Withers, Stephen G.</creatorcontrib><creatorcontrib>Liggins, Richard</creatorcontrib><title>Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Bioavailability</subject><subject>Biological Availability</subject><subject>Difluorosialic acid</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Half-Life</subject><subject>Mice</subject><subject>Neuraminidase - antagonists & inhibitors</subject><subject>Neuraminidase - metabolism</subject><subject>Neuraminidase inhibitor</subject><subject>Prodrug</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Sialic Acids - chemical synthesis</subject><subject>Sialic Acids - chemistry</subject><subject>Sialic Acids - pharmacokinetics</subject><subject>Snapshot PK screen</subject><subject>Viral Proteins - antagonists & inhibitors</subject><subject>Viral Proteins - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNp9kU9v1DAQxS0EotvCF-CAfORAgh3b-SNxqSqgiEpwAImb5diT7qySePE4K-2X4DOT7RaOnCyNfu-N3zzGXklRSiHrd7uyn_xYVkKaUuhSmO4J20hd60JpYZ6yjehqUbSd_nnBLol2QkgttH7OLirTtaKTYsN-XxMBEc73PG-Bx-RG3mN0B4ej63HEfORx4AGHcYkpEroRPXceA9-nGNJyT2_5PmaYMz_gST3DktyEMwZHwHHeYo85phVbHtY4TrPb0zZm_u0LJ58A5oc5kTu-YM8GNxK8fHyv2I-PH77f3BZ3Xz99vrm-K7wydS6Cl2taqVopoXYDyLpujGxdHZrQ9MYAmFYrVYW-M06oVjnXDD2IoeorAx7UFXtz9l1D_FqAsp2QPIyjmyEuZGXdKmUapasVrc6oX-NTgsHuE04uHa0U9tSD3dlTD_bUgxXarj9bRa8f_Zd-gvBP8vfwK_D-DMCa8oCQLHmE2UPABD7bEPF__n8AqNWc-g</recordid><startdate>20150615</startdate><enddate>20150615</enddate><creator>Arns, Steve</creator><creator>Tan, Jason</creator><creator>Sun, Sharon</creator><creator>Galey, Adam</creator><creator>Zisman, Natalia</creator><creator>Ross, Fiona</creator><creator>Udechukwu, Jenna</creator><creator>Dercho, Samantha</creator><creator>Gusti, Vionarica</creator><creator>Paquette, Jay</creator><creator>Webb, Murray</creator><creator>Bourque, Elyse</creator><creator>Withers, Stephen G.</creator><creator>Liggins, Richard</creator><general>Elsevier Ltd</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>20150615</creationdate><title>Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay</title><author>Arns, Steve ; Tan, Jason ; Sun, Sharon ; Galey, Adam ; Zisman, Natalia ; Ross, Fiona ; Udechukwu, Jenna ; Dercho, Samantha ; Gusti, Vionarica ; Paquette, Jay ; Webb, Murray ; Bourque, Elyse ; Withers, Stephen G. ; Liggins, Richard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-dc105913811e6afe1667518a6d7d7b55ee584332db95a0383aa7fbe0f2b25ece3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Bioavailability</topic><topic>Biological Availability</topic><topic>Difluorosialic acid</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Half-Life</topic><topic>Mice</topic><topic>Neuraminidase - antagonists & inhibitors</topic><topic>Neuraminidase - metabolism</topic><topic>Neuraminidase inhibitor</topic><topic>Prodrug</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacokinetics</topic><topic>Sialic Acids - chemical synthesis</topic><topic>Sialic Acids - chemistry</topic><topic>Sialic Acids - pharmacokinetics</topic><topic>Snapshot PK screen</topic><topic>Viral Proteins - antagonists & inhibitors</topic><topic>Viral Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Arns, Steve</creatorcontrib><creatorcontrib>Tan, Jason</creatorcontrib><creatorcontrib>Sun, Sharon</creatorcontrib><creatorcontrib>Galey, Adam</creatorcontrib><creatorcontrib>Zisman, Natalia</creatorcontrib><creatorcontrib>Ross, Fiona</creatorcontrib><creatorcontrib>Udechukwu, Jenna</creatorcontrib><creatorcontrib>Dercho, Samantha</creatorcontrib><creatorcontrib>Gusti, Vionarica</creatorcontrib><creatorcontrib>Paquette, Jay</creatorcontrib><creatorcontrib>Webb, Murray</creatorcontrib><creatorcontrib>Bourque, Elyse</creatorcontrib><creatorcontrib>Withers, Stephen G.</creatorcontrib><creatorcontrib>Liggins, Richard</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arns, Steve</au><au>Tan, Jason</au><au>Sun, Sharon</au><au>Galey, Adam</au><au>Zisman, Natalia</au><au>Ross, Fiona</au><au>Udechukwu, Jenna</au><au>Dercho, Samantha</au><au>Gusti, Vionarica</au><au>Paquette, Jay</au><au>Webb, Murray</au><au>Bourque, Elyse</au><au>Withers, Stephen G.</au><au>Liggins, Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-06-15</date><risdate>2015</risdate><volume>25</volume><issue>12</issue><spage>2505</spage><epage>2509</epage><pages>2505-2509</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>[Display omitted]
Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25980910</pmid><doi>10.1016/j.bmcl.2015.04.059</doi><tpages>5</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2015-06, Vol.25 (12), p.2505-2509 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | ScienceDirect Freedom Collection |
| subjects | Administration, Oral Animals Bioavailability Biological Availability Difluorosialic acid Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Half-Life Mice Neuraminidase - antagonists & inhibitors Neuraminidase - metabolism Neuraminidase inhibitor Prodrug Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacokinetics Sialic Acids - chemical synthesis Sialic Acids - chemistry Sialic Acids - pharmacokinetics Snapshot PK screen Viral Proteins - antagonists & inhibitors Viral Proteins - metabolism |
| title | Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay |
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