Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase
Several 2′-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2′-Deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improv...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-03, Vol.57 (6), p.2582-2588 |
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| container_title | Journal of medicinal chemistry |
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| creator | Ferraris, Dana Duvall, Bridget Delahanty, Greg Mistry, Bipin Alt, Jesse Rojas, Camilo Rowbottom, Christopher Sanders, Kristen Schuck, Edgar Huang, Kuan-Chun Redkar, Sanjeev Slusher, Barbara B Tsukamoto, Takashi |
| description | Several 2′-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2′-Deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism. |
| doi_str_mv | 10.1021/jm401856k |
| format | Article |
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(4R)-2′-Deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm401856k</identifier><identifier>PMID: 24520856</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Azacitidine - analogs & derivatives ; Azacitidine - pharmacology ; Biological Availability ; Cytidine Deaminase - antagonists & inhibitors ; Drug Design ; Drug Stability ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Excitatory Postsynaptic Potentials ; Fluorine ; Gastric Juice - chemistry ; Macaca mulatta ; Models, Molecular ; Molecular Conformation ; Structure-Activity Relationship ; Tetrahydrouridine - analogs & derivatives ; Tetrahydrouridine - chemical synthesis ; Tetrahydrouridine - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2014-03, Vol.57 (6), p.2582-2588</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-bae7ac9beda0d1803b7dc493219a0676ed03eaec4e9c8c4785b4d6d32aa333683</citedby><cites>FETCH-LOGICAL-a315t-bae7ac9beda0d1803b7dc493219a0676ed03eaec4e9c8c4785b4d6d32aa333683</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/jm401856k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm401856k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24520856$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferraris, Dana</creatorcontrib><creatorcontrib>Duvall, Bridget</creatorcontrib><creatorcontrib>Delahanty, Greg</creatorcontrib><creatorcontrib>Mistry, Bipin</creatorcontrib><creatorcontrib>Alt, Jesse</creatorcontrib><creatorcontrib>Rojas, Camilo</creatorcontrib><creatorcontrib>Rowbottom, Christopher</creatorcontrib><creatorcontrib>Sanders, Kristen</creatorcontrib><creatorcontrib>Schuck, Edgar</creatorcontrib><creatorcontrib>Huang, Kuan-Chun</creatorcontrib><creatorcontrib>Redkar, Sanjeev</creatorcontrib><creatorcontrib>Slusher, Barbara B</creatorcontrib><creatorcontrib>Tsukamoto, Takashi</creatorcontrib><title>Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Several 2′-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2′-Deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.</description><subject>Animals</subject><subject>Azacitidine - analogs & derivatives</subject><subject>Azacitidine - pharmacology</subject><subject>Biological Availability</subject><subject>Cytidine Deaminase - antagonists & inhibitors</subject><subject>Drug Design</subject><subject>Drug Stability</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Excitatory Postsynaptic Potentials</subject><subject>Fluorine</subject><subject>Gastric Juice - chemistry</subject><subject>Macaca mulatta</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydrouridine - analogs & derivatives</subject><subject>Tetrahydrouridine - chemical synthesis</subject><subject>Tetrahydrouridine - 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>eNpt0E1LAzEQBuAgitbqwT8guQgKruZjP4_S-lEQFNTzMptMbepuosluoVd_uZGqJ08zh2demJeQI84uOBP8ctmljJdZ_rZFRjwTLElLlm6TEWNCJCIXco_sh7BkjEku5C7ZE2lU8WBEPqcYzKs9p09r2y_iHs4pWE0fF-A7UK51r0ZBS69X0A7QG2epm9ObdnDeWOhR02fsPSzW2rvBG20s0il6s4p2hYFCoDO7MI3pnQ_fp5N1_6ugixEBD8jOHNqAhz9zTF5urp8nd8n9w-1scnWfgORZnzSABaiqQQ1M85LJptAqraTgFbC8yFEziYAqxUqVKi3KrEl1rqUAkFLmpRyT003uu3cfA4a-7kxQ2LZg0Q2h5hnnsiqYKCI921DlXQge5_W7Nx34dc1Z_V15_Vd5tMc_sUPTof6Tvx1HcLIBoEK9jC3Z-OU_QV8hw4ql</recordid><startdate>20140327</startdate><enddate>20140327</enddate><creator>Ferraris, Dana</creator><creator>Duvall, Bridget</creator><creator>Delahanty, Greg</creator><creator>Mistry, Bipin</creator><creator>Alt, Jesse</creator><creator>Rojas, Camilo</creator><creator>Rowbottom, Christopher</creator><creator>Sanders, Kristen</creator><creator>Schuck, Edgar</creator><creator>Huang, Kuan-Chun</creator><creator>Redkar, Sanjeev</creator><creator>Slusher, Barbara B</creator><creator>Tsukamoto, Takashi</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>20140327</creationdate><title>Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase</title><author>Ferraris, Dana ; Duvall, Bridget ; Delahanty, Greg ; Mistry, Bipin ; Alt, Jesse ; Rojas, Camilo ; Rowbottom, Christopher ; Sanders, Kristen ; Schuck, Edgar ; Huang, Kuan-Chun ; Redkar, Sanjeev ; Slusher, Barbara B ; Tsukamoto, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-bae7ac9beda0d1803b7dc493219a0676ed03eaec4e9c8c4785b4d6d32aa333683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Azacitidine - analogs & derivatives</topic><topic>Azacitidine - pharmacology</topic><topic>Biological Availability</topic><topic>Cytidine Deaminase - antagonists & inhibitors</topic><topic>Drug Design</topic><topic>Drug Stability</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Excitatory Postsynaptic Potentials</topic><topic>Fluorine</topic><topic>Gastric Juice - chemistry</topic><topic>Macaca mulatta</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydrouridine - analogs & derivatives</topic><topic>Tetrahydrouridine - chemical synthesis</topic><topic>Tetrahydrouridine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferraris, Dana</creatorcontrib><creatorcontrib>Duvall, Bridget</creatorcontrib><creatorcontrib>Delahanty, Greg</creatorcontrib><creatorcontrib>Mistry, Bipin</creatorcontrib><creatorcontrib>Alt, Jesse</creatorcontrib><creatorcontrib>Rojas, Camilo</creatorcontrib><creatorcontrib>Rowbottom, Christopher</creatorcontrib><creatorcontrib>Sanders, Kristen</creatorcontrib><creatorcontrib>Schuck, Edgar</creatorcontrib><creatorcontrib>Huang, Kuan-Chun</creatorcontrib><creatorcontrib>Redkar, Sanjeev</creatorcontrib><creatorcontrib>Slusher, Barbara B</creatorcontrib><creatorcontrib>Tsukamoto, Takashi</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>Ferraris, Dana</au><au>Duvall, Bridget</au><au>Delahanty, Greg</au><au>Mistry, Bipin</au><au>Alt, Jesse</au><au>Rojas, Camilo</au><au>Rowbottom, Christopher</au><au>Sanders, Kristen</au><au>Schuck, Edgar</au><au>Huang, Kuan-Chun</au><au>Redkar, Sanjeev</au><au>Slusher, Barbara B</au><au>Tsukamoto, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Azacitidine - analogs & derivatives Azacitidine - pharmacology Biological Availability Cytidine Deaminase - antagonists & inhibitors Drug Design Drug Stability Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Excitatory Postsynaptic Potentials Fluorine Gastric Juice - chemistry Macaca mulatta Models, Molecular Molecular Conformation Structure-Activity Relationship Tetrahydrouridine - analogs & derivatives Tetrahydrouridine - chemical synthesis Tetrahydrouridine - pharmacology |
| title | Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase |
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