Elucidation of fluorine's impact on pKa and in vitro Pgp-mediated efflux for a series of PDE9 inhibitors

Kasper Fjelbye, Mauro Marigo, Rasmus P. Clausen, Erling B. Jørgensen, Claus T. Christoffersen, Karsten Juhl*

*Corresponding author for this work
6 Citations (Scopus)

Abstract

P-Glycoprotein (Pgp)-mediated cellular efflux is recognized as a common challenge in CNS drug discovery. In this study, the influence of replacing a hydrogen atom with fluorine on the pKa and Pgp-mediated efflux is elucidated for a series of PDE9 inhibitors. The PDE9 inhibitors with and without fluorine were synthesized using a novel condensation-oxidation approach, providing access to several analogues, all from the same stereoenriched aldehyde building block. The incorporation of fluorine was found to influence two acid-base functionalities concomitantly, both of which were involved in Pgp-recognition. By methylating the acidic functionality, it was possible to isolate the effect responsible for lowering the Pgp-mediated efflux.

Original languageEnglish
JournalMedChemComm
Volume9
Issue number5
Pages (from-to)893-896
Number of pages4
ISSN2040-2503
DOIs
Publication statusPublished - 2018

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