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 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.
Highlights
Depression is a common mental disease estimated to affect some 350 million people worldwide [1].a World Mental Health Survey conducted in 17 countries in 2012 found that about 5% of people reported having an episode of depression in the previous year [2]
Acyl chlorides a–o were synthesized from the corresponding carboxylic acids by reaction with SOCl2 in pyridine at 90 °C for 3 h [27]
Compounds 1a–o were synthesized by treatment of ODV with the corresponding acyl chloride in the presence of anhydrous pyridine and THF at 0–25 C for 6 h (Scheme 2)
Summary
Depression is a common mental disease estimated to affect some 350 million people worldwide [1]. A World Mental Health Survey conducted in 17 countries in 2012 found that about 5% of people reported having an episode of depression in the previous year [2]. The condition displays a high rate of lifetime incidence, early age onset, high chronicity and significant role impairment. Despite a wide range of pharmacotherapeutic options, response to antidepressant medication is subject to delayed onset and is highly variable. It is not without significant adverse effects. The search for improved antidepressant drugs remains an ongoing concern
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