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

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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.

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

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Publication details

The article was received on 28 Feb 2018, accepted on 15 Apr 2018 and first published on 28 Apr 2018


Article type: Research Article
DOI: 10.1039/C8MD00114F
Citation: Med. Chem. Commun., 2018, Advance Article
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    Elucidation of fluorine's impact on pKa and in vitro Pgp-mediated efflux for a series of PDE9 inhibitors

    K. Fjelbye, M. Marigo, R. P. Clausen, E. B. Jørgensen, C. T. Christoffersen and K. Juhl, Med. Chem. Commun., 2018, Advance Article , DOI: 10.1039/C8MD00114F

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