Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake
O-Desmethylvenlafaxine (desvenlafaxine, ODV) is a recently approved antidepressant which in some clinical studies failed to meet a satisfactory end-point. The aim of this study was to prepare a series of phenolic esters of ODV and evaluate their potential as ODV prodrugs with improved brain uptake....
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MDPI AG
2013-12-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/18/12/14920 |
| _version_ | 1817995654502285312 |
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| author | Yang Zhang Yan Yang Sen Zhao Zhichao Yang Hong Yang J. Paul Fawcett Youxin Li Jingkai Gu Tiemin Sun |
| author_facet | Yang Zhang Yan Yang Sen Zhao Zhichao Yang Hong Yang J. Paul Fawcett Youxin Li Jingkai Gu Tiemin Sun |
| author_sort | Yang Zhang |
| collection | DOAJ |
| description | O-Desmethylvenlafaxine (desvenlafaxine, ODV) is a recently approved antidepressant which in some clinical studies failed to meet a satisfactory end-point. The aim of this study was to prepare a series of phenolic esters of ODV and evaluate their potential as ODV prodrugs with improved brain uptake. Fifteen phenolic esters (compounds 1a–o) were synthesized and their pharmacokinetic profiles evaluated in rat. The four compounds producing the highest relative bioavailability of ODV in rat (compounds 1c, 1e, 1n, 1o) were then studied to evaluate their brain uptake. Of these four compounds, compound 1n (the piperonylic acid ester of ODV) demonstrated the highest Cmax of ODV both in the rat hypothalamus and total brain. Finally the pharmacokinetics of 1n were evaluated in beagle dog where the increase in relative bioavailability of ODV was found to be as great as in rat. This high relative bioavailability of ODV coupled with its good brain penetration make 1n the most promising candidate for development as an ODV prodrug. |
| first_indexed | 2024-04-14T02:08:55Z |
| format | Article |
| id | doaj.art-2536e831fb0d4be5869842c04dcd4689 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-14T02:08:55Z |
| publishDate | 2013-12-01 |
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| series | Molecules |
| spelling | doaj.art-2536e831fb0d4be5869842c04dcd46892022-12-22T02:18:29ZengMDPI AGMolecules1420-30492013-12-011812149201493410.3390/molecules181214920molecules181214920Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain UptakeYang Zhang0Yan Yang1Sen Zhao2Zhichao Yang3Hong Yang4J. Paul Fawcett5Youxin Li6Jingkai Gu7Tiemin Sun8Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, ChinaResearch Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, ChinaResearch Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, ChinaResearch Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, ChinaResearch Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, ChinaSchool of Pharmacy, University of Otago, PO Box 56, Dunedin 9054, New ZealandResearch Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, ChinaResearch Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, ChinaKey Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, ChinaO-Desmethylvenlafaxine (desvenlafaxine, ODV) is a recently approved antidepressant which in some clinical studies failed to meet a satisfactory end-point. The aim of this study was to prepare a series of phenolic esters of ODV and evaluate their potential as ODV prodrugs with improved brain uptake. Fifteen phenolic esters (compounds 1a–o) were synthesized and their pharmacokinetic profiles evaluated in rat. The four compounds producing the highest relative bioavailability of ODV in rat (compounds 1c, 1e, 1n, 1o) were then studied to evaluate their brain uptake. Of these four compounds, compound 1n (the piperonylic acid ester of ODV) demonstrated the highest Cmax of ODV both in the rat hypothalamus and total brain. Finally the pharmacokinetics of 1n were evaluated in beagle dog where the increase in relative bioavailability of ODV was found to be as great as in rat. This high relative bioavailability of ODV coupled with its good brain penetration make 1n the most promising candidate for development as an ODV prodrug.http://www.mdpi.com/1420-3049/18/12/14920O-desmethylvenlafaxinephenolic esterprodrugpharmacokineticsbrain uptakeratdog |
| spellingShingle | Yang Zhang Yan Yang Sen Zhao Zhichao Yang Hong Yang J. Paul Fawcett Youxin Li Jingkai Gu Tiemin Sun Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake Molecules O-desmethylvenlafaxine phenolic ester prodrug pharmacokinetics brain uptake rat dog |
| title | Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake |
| title_full | Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake |
| title_fullStr | Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake |
| title_full_unstemmed | Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake |
| title_short | Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake |
| title_sort | phenolic esters of o desmethylvenlafaxine with improved oral bioavailability and brain uptake |
| topic | O-desmethylvenlafaxine phenolic ester prodrug pharmacokinetics brain uptake rat dog |
| url | http://www.mdpi.com/1420-3049/18/12/14920 |
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