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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

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.

OriginalsprogEngelsk
TidsskriftMedChemComm
Vol/bind9
Udgave nummer5
Sider (fra-til)893-896
Antal sider4
ISSN2040-2503
DOI
StatusUdgivet - 2018

ID: 211808783