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

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.

SUBMITTER: Fjelbye K 

PROVIDER: S-EPMC6071825 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Elucidation of fluorine's impact on p<i>K</i><sub>a</sub> and <i>in vitro</i> Pgp-mediated efflux for a series of PDE9 inhibitors.

Fjelbye Kasper K   Marigo Mauro M   Clausen Rasmus P RP   Jørgensen Erling B EB   Christoffersen Claus T CT   Juhl Karsten K  

MedChemComm 20180428 5

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 p<i>K</i><sub>a</sub> 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 incorporatio  ...[more]