title: Phenolic esters of O-desmethylvenlafaxine with improved oral bioavailability and brain uptake.
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 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.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China. gujk@jlu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Sen
authors.initials: S
authors.lastname: Zhao
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: J Paul
authors.initials: JP
authors.lastname: Fawcett
authors.forename: Youxin
authors.initials: Y
authors.lastname: Li
authors.forename: Jingkai
authors.initials: J
authors.lastname: Gu
authors.forename: Tiemin
authors.initials: T
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D003511:Cyclohexanols / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D000069468:Desvenlafaxine Succinate; D004285:Dogs; D004952:Esters; D011355:Prodrugs; D051381:Rats
chemical_list: D003511:Cyclohexanols; D004952:Esters; D011355:Prodrugs; D000069468:Desvenlafaxine Succinate