Discovery of a 2′-fluoro-2′-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties
[Display omitted] A series of 2′-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2′-fluoro-2′-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistanc...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-04, Vol.27 (8), p.1840-1847 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Kirschberg, Thorsten A. Metobo, Sammy Clarke, Michael O. Aktoudianakis, Vangelis Babusis, Darius Barauskas, Ona Birkus, Gabriel Butler, Thomas Byun, Daniel Chin, Gregory Doerffler, Edward Edwards, Thomas E. Fenaux, Martijn Lee, Rick Lew, Willard Mish, Michael R. Murakami, Eisuke Park, Yeojin Squires, Neil H. Tirunagari, Neeraj Wang, Ting Whitcomb, Mark Xu, Jie Yang, Huiling Ye, Hong Zhang, Lijun Appleby, Todd C. Feng, Joy Y. Ray, Adrian S. Cho, Aesop Kim, Choung U. |
| description | [Display omitted]
A series of 2′-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2′-fluoro-2′-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals. |
| doi_str_mv | 10.1016/j.bmcl.2017.02.037 |
| format | Article |
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A series of 2′-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2′-fluoro-2′-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.02.037</identifier><identifier>PMID: 28274633</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Amides - chemistry ; Amides - pharmacokinetics ; Amides - pharmacology ; Animals ; Antiviral ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacokinetics ; Antiviral Agents - pharmacology ; C-nucleoside ; Caco-2 Cells ; Cell Line ; Cricetinae ; Drug Discovery ; Drug Resistance, Viral ; Halogenation ; Hepacivirus - drug effects ; Hepacivirus - genetics ; Hepacivirus - physiology ; Hepatitis C ; Hepatitis C - drug therapy ; Humans ; Methylation ; Molecular Docking Simulation ; NS5B polymerase ; Nucleosides - chemistry ; Nucleosides - pharmacokinetics ; Nucleosides - pharmacology ; Phosphoric Acids - chemistry ; Phosphoric Acids - pharmacokinetics ; Phosphoric Acids - pharmacology ; Point Mutation ; Prodrugs - chemistry ; Prodrugs - pharmacokinetics ; Prodrugs - pharmacology ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - genetics ; Viral Nonstructural Proteins - metabolism ; Virus Replication - drug effects</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-04, Vol.27 (8), p.1840-1847</ispartof><rights>2017</rights><rights>Copyright © 2017. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c383t-5bcc971e213cb78d50039a8bd45cb05d394b5297c806e123f130de167f2d11983</citedby><cites>FETCH-LOGICAL-c383t-5bcc971e213cb78d50039a8bd45cb05d394b5297c806e123f130de167f2d11983</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X17301701$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28274633$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1438904$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Kirschberg, Thorsten A.</creatorcontrib><creatorcontrib>Metobo, Sammy</creatorcontrib><creatorcontrib>Clarke, Michael O.</creatorcontrib><creatorcontrib>Aktoudianakis, Vangelis</creatorcontrib><creatorcontrib>Babusis, Darius</creatorcontrib><creatorcontrib>Barauskas, Ona</creatorcontrib><creatorcontrib>Birkus, Gabriel</creatorcontrib><creatorcontrib>Butler, Thomas</creatorcontrib><creatorcontrib>Byun, Daniel</creatorcontrib><creatorcontrib>Chin, Gregory</creatorcontrib><creatorcontrib>Doerffler, Edward</creatorcontrib><creatorcontrib>Edwards, Thomas E.</creatorcontrib><creatorcontrib>Fenaux, Martijn</creatorcontrib><creatorcontrib>Lee, Rick</creatorcontrib><creatorcontrib>Lew, Willard</creatorcontrib><creatorcontrib>Mish, Michael R.</creatorcontrib><creatorcontrib>Murakami, Eisuke</creatorcontrib><creatorcontrib>Park, Yeojin</creatorcontrib><creatorcontrib>Squires, Neil H.</creatorcontrib><creatorcontrib>Tirunagari, Neeraj</creatorcontrib><creatorcontrib>Wang, Ting</creatorcontrib><creatorcontrib>Whitcomb, Mark</creatorcontrib><creatorcontrib>Xu, Jie</creatorcontrib><creatorcontrib>Yang, Huiling</creatorcontrib><creatorcontrib>Ye, Hong</creatorcontrib><creatorcontrib>Zhang, Lijun</creatorcontrib><creatorcontrib>Appleby, Todd C.</creatorcontrib><creatorcontrib>Feng, Joy Y.</creatorcontrib><creatorcontrib>Ray, Adrian S.</creatorcontrib><creatorcontrib>Cho, Aesop</creatorcontrib><creatorcontrib>Kim, Choung U.</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Discovery of a 2′-fluoro-2′-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
A series of 2′-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2′-fluoro-2′-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.</description><subject>Amides - chemistry</subject><subject>Amides - pharmacokinetics</subject><subject>Amides - pharmacology</subject><subject>Animals</subject><subject>Antiviral</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Antiviral Agents - pharmacology</subject><subject>C-nucleoside</subject><subject>Caco-2 Cells</subject><subject>Cell Line</subject><subject>Cricetinae</subject><subject>Drug Discovery</subject><subject>Drug Resistance, Viral</subject><subject>Halogenation</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - genetics</subject><subject>Hepacivirus - physiology</subject><subject>Hepatitis C</subject><subject>Hepatitis C - drug therapy</subject><subject>Humans</subject><subject>Methylation</subject><subject>Molecular Docking Simulation</subject><subject>NS5B polymerase</subject><subject>Nucleosides - chemistry</subject><subject>Nucleosides - pharmacokinetics</subject><subject>Nucleosides - pharmacology</subject><subject>Phosphoric Acids - chemistry</subject><subject>Phosphoric Acids - pharmacokinetics</subject><subject>Phosphoric Acids - pharmacology</subject><subject>Point Mutation</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - pharmacology</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - genetics</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>Virus Replication - drug effects</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtu1DAUhi1ERYfCC7BAFnuH40tuEhsULkWq1A0gdlZinxCPkjiyPYNmx4oH4pH6JCQdYNmFZev4v-h8hLzgkHHgxet91k1mzATwMgORgSwfkR1XhWJSQf6Y7KAugFW1-nZJnsa4B-AKlHpCLkUlSlVIuSO_3rlo_BHDifqetlTc_fzN-vHgg2f374ZNmIbTSBs2H8yIPjmL9Lr5Shc_niYMbUTq5sF1LvlA29muKcvg43pCOznbJqRL8DYcvtMfLg20b4_rTzfejxcMyWF8Ri76doz4_O99Rb58eP-5uWY3tx8_NW9vmJGVTCzvjKlLjoJL05WVzQFk3VadVbnpILeyVl0u6tJUUCAXsucSLPKi7IXlvK7kFXl1zvUxOR2NS2gG4-cZTdJcyaoGtYrEWWSCjzFgr5fgpjacNAe9kdd7vZHXG3kNQq_kV9PLs2k5dBPa_5Z_qFfBm7MA1_2ODsNWj7NB68LWbr17KP8PmdaXyA</recordid><startdate>20170415</startdate><enddate>20170415</enddate><creator>Kirschberg, Thorsten A.</creator><creator>Metobo, Sammy</creator><creator>Clarke, Michael O.</creator><creator>Aktoudianakis, Vangelis</creator><creator>Babusis, Darius</creator><creator>Barauskas, Ona</creator><creator>Birkus, Gabriel</creator><creator>Butler, Thomas</creator><creator>Byun, Daniel</creator><creator>Chin, Gregory</creator><creator>Doerffler, Edward</creator><creator>Edwards, Thomas E.</creator><creator>Fenaux, Martijn</creator><creator>Lee, Rick</creator><creator>Lew, Willard</creator><creator>Mish, Michael R.</creator><creator>Murakami, Eisuke</creator><creator>Park, Yeojin</creator><creator>Squires, Neil H.</creator><creator>Tirunagari, Neeraj</creator><creator>Wang, Ting</creator><creator>Whitcomb, Mark</creator><creator>Xu, Jie</creator><creator>Yang, Huiling</creator><creator>Ye, Hong</creator><creator>Zhang, Lijun</creator><creator>Appleby, Todd C.</creator><creator>Feng, Joy Y.</creator><creator>Ray, Adrian S.</creator><creator>Cho, Aesop</creator><creator>Kim, Choung U.</creator><general>Elsevier Ltd</general><general>Elsevier</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>OTOTI</scope></search><sort><creationdate>20170415</creationdate><title>Discovery of a 2′-fluoro-2′-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties</title><author>Kirschberg, Thorsten A. ; Metobo, Sammy ; Clarke, Michael O. ; Aktoudianakis, Vangelis ; Babusis, Darius ; Barauskas, Ona ; Birkus, Gabriel ; Butler, Thomas ; Byun, Daniel ; Chin, Gregory ; Doerffler, Edward ; Edwards, Thomas E. ; Fenaux, Martijn ; Lee, Rick ; Lew, Willard ; Mish, Michael R. ; Murakami, Eisuke ; Park, Yeojin ; Squires, Neil H. ; Tirunagari, Neeraj ; Wang, Ting ; Whitcomb, Mark ; Xu, Jie ; Yang, Huiling ; Ye, Hong ; Zhang, Lijun ; Appleby, Todd C. ; Feng, Joy Y. ; Ray, Adrian S. ; Cho, Aesop ; Kim, Choung U.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-5bcc971e213cb78d50039a8bd45cb05d394b5297c806e123f130de167f2d11983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Amides - chemistry</topic><topic>Amides - pharmacokinetics</topic><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>Antiviral</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacokinetics</topic><topic>Antiviral Agents - pharmacology</topic><topic>C-nucleoside</topic><topic>Caco-2 Cells</topic><topic>Cell Line</topic><topic>Cricetinae</topic><topic>Drug Discovery</topic><topic>Drug Resistance, Viral</topic><topic>Halogenation</topic><topic>Hepacivirus - drug effects</topic><topic>Hepacivirus - genetics</topic><topic>Hepacivirus - physiology</topic><topic>Hepatitis C</topic><topic>Hepatitis C - drug therapy</topic><topic>Humans</topic><topic>Methylation</topic><topic>Molecular Docking Simulation</topic><topic>NS5B polymerase</topic><topic>Nucleosides - chemistry</topic><topic>Nucleosides - pharmacokinetics</topic><topic>Nucleosides - pharmacology</topic><topic>Phosphoric Acids - chemistry</topic><topic>Phosphoric Acids - pharmacokinetics</topic><topic>Phosphoric Acids - pharmacology</topic><topic>Point Mutation</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacokinetics</topic><topic>Prodrugs - pharmacology</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - genetics</topic><topic>Viral Nonstructural Proteins - metabolism</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kirschberg, Thorsten A.</creatorcontrib><creatorcontrib>Metobo, Sammy</creatorcontrib><creatorcontrib>Clarke, Michael O.</creatorcontrib><creatorcontrib>Aktoudianakis, Vangelis</creatorcontrib><creatorcontrib>Babusis, Darius</creatorcontrib><creatorcontrib>Barauskas, Ona</creatorcontrib><creatorcontrib>Birkus, Gabriel</creatorcontrib><creatorcontrib>Butler, Thomas</creatorcontrib><creatorcontrib>Byun, Daniel</creatorcontrib><creatorcontrib>Chin, Gregory</creatorcontrib><creatorcontrib>Doerffler, Edward</creatorcontrib><creatorcontrib>Edwards, Thomas E.</creatorcontrib><creatorcontrib>Fenaux, Martijn</creatorcontrib><creatorcontrib>Lee, Rick</creatorcontrib><creatorcontrib>Lew, Willard</creatorcontrib><creatorcontrib>Mish, Michael R.</creatorcontrib><creatorcontrib>Murakami, Eisuke</creatorcontrib><creatorcontrib>Park, Yeojin</creatorcontrib><creatorcontrib>Squires, Neil H.</creatorcontrib><creatorcontrib>Tirunagari, Neeraj</creatorcontrib><creatorcontrib>Wang, Ting</creatorcontrib><creatorcontrib>Whitcomb, Mark</creatorcontrib><creatorcontrib>Xu, Jie</creatorcontrib><creatorcontrib>Yang, Huiling</creatorcontrib><creatorcontrib>Ye, Hong</creatorcontrib><creatorcontrib>Zhang, Lijun</creatorcontrib><creatorcontrib>Appleby, Todd C.</creatorcontrib><creatorcontrib>Feng, Joy Y.</creatorcontrib><creatorcontrib>Ray, Adrian S.</creatorcontrib><creatorcontrib>Cho, Aesop</creatorcontrib><creatorcontrib>Kim, Choung U.</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>OSTI.GOV</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kirschberg, Thorsten A.</au><au>Metobo, Sammy</au><au>Clarke, Michael O.</au><au>Aktoudianakis, Vangelis</au><au>Babusis, Darius</au><au>Barauskas, Ona</au><au>Birkus, Gabriel</au><au>Butler, Thomas</au><au>Byun, Daniel</au><au>Chin, Gregory</au><au>Doerffler, Edward</au><au>Edwards, Thomas E.</au><au>Fenaux, Martijn</au><au>Lee, Rick</au><au>Lew, Willard</au><au>Mish, Michael R.</au><au>Murakami, Eisuke</au><au>Park, Yeojin</au><au>Squires, Neil H.</au><au>Tirunagari, Neeraj</au><au>Wang, Ting</au><au>Whitcomb, Mark</au><au>Xu, Jie</au><au>Yang, Huiling</au><au>Ye, Hong</au><au>Zhang, Lijun</au><au>Appleby, Todd C.</au><au>Feng, Joy Y.</au><au>Ray, Adrian S.</au><au>Cho, Aesop</au><au>Kim, Choung U.</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a 2′-fluoro-2′-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-04-15</date><risdate>2017</risdate><volume>27</volume><issue>8</issue><spage>1840</spage><epage>1847</epage><pages>1840-1847</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
A series of 2′-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2′-fluoro-2′-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28274633</pmid><doi>10.1016/j.bmcl.2017.02.037</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2017-04, Vol.27 (8), p.1840-1847 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1438904 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Amides - chemistry Amides - pharmacokinetics Amides - pharmacology Animals Antiviral Antiviral Agents - chemistry Antiviral Agents - pharmacokinetics Antiviral Agents - pharmacology C-nucleoside Caco-2 Cells Cell Line Cricetinae Drug Discovery Drug Resistance, Viral Halogenation Hepacivirus - drug effects Hepacivirus - genetics Hepacivirus - physiology Hepatitis C Hepatitis C - drug therapy Humans Methylation Molecular Docking Simulation NS5B polymerase Nucleosides - chemistry Nucleosides - pharmacokinetics Nucleosides - pharmacology Phosphoric Acids - chemistry Phosphoric Acids - pharmacokinetics Phosphoric Acids - pharmacology Point Mutation Prodrugs - chemistry Prodrugs - pharmacokinetics Prodrugs - pharmacology Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - genetics Viral Nonstructural Proteins - metabolism Virus Replication - drug effects |
| title | Discovery of a 2′-fluoro-2′-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties |
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