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Molecules 2013, 18(12), 14920-14934; doi:10.3390/molecules181214920
Article

Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake

1,2,3, 2, 2, 2, 2, 4, 2, 2,*  and 1,*
1 Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China 2 Research Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, China 3 School of Chemical and Pharmaceutical Engineering, Jilin Institute of Chemical Technology, Jilin 132022, China 4 School of Pharmacy, University of Otago, PO Box 56, Dunedin 9054, New Zealand
* Authors to whom correspondence should be addressed.
Received: 30 October 2013 / Revised: 2 December 2013 / Accepted: 2 December 2013 / Published: 4 December 2013
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Abstract

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 1ao) 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.
Keywords: O-desmethylvenlafaxine; phenolic ester; prodrug; pharmacokinetics; brain uptake; rat; dog O-desmethylvenlafaxine; phenolic ester; prodrug; pharmacokinetics; brain uptake; rat; dog
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Zhang, Y.; Yang, Y.; Zhao, S.; Yang, Z.; Yang, H.; Fawcett, J.P.; Li, Y.; Gu, J.; Sun, T. Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake. Molecules 2013, 18, 14920-14934.

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