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

Molecules

Yang Zhang¹  Yan Yang³  Sen Zhao³  Zhichao Yang³  Hong Yang³  J. Paul Fawcett²  Youxin Li³  Jingkai Gu³ 

[1] Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China;School of Pharmacy, University of Otago, PO Box 56, Dunedin 9054, New Zealand;Research Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun 130021, China

关键词: O-desmethylvenlafaxine;    phenolic ester;    prodrug;    pharmacokinetics;    brain uptake;    rat;    dog;   

DOI  :  10.3390/molecules181214920

来源: mdpi

【 摘 要 】

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 C_max 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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.