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 language | English |
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Journal | MedChemComm |
Volume | 9 |
Issue number | 5 |
Pages (from-to) | 893-896 |
Number of pages | 4 |
ISSN | 2040-2503 |
DOIs | |
Publication status | Published - 2018 |