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

doi:10.1039/c8md00114f

Elucidation of fluorine's impact on pK_a 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 af dette arbejde

Kemisk Institut

6 Citationer (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 pK_a 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.

Originalsprog	Engelsk
Tidsskrift	MedChemComm
Vol/bind	9
Udgave nummer	5
Sider (fra-til)	893-896
Antal sider	4
ISSN	2040-2503
DOI	https://doi.org/10.1039/c8md00114f
Status	Udgivet - 2018

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10.1039/c8md00114f

Citationsformater

@article{00ed8ff899114a139c42473010250fa8,

title = "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.",

author = "Kasper Fjelbye and Mauro Marigo and Clausen, {Rasmus P.} and J{\o}rgensen, {Erling B.} and Christoffersen, {Claus T.} and Karsten Juhl",

year = "2018",

doi = "10.1039/c8md00114f",

language = "English",

volume = "9",

pages = "893--896",

journal = "MedChemComm",

issn = "2040-2503",

publisher = "Royal Society of Chemistry",

number = "5",

}

TY - JOUR

T1 - Elucidation of fluorine's impact on pKa and in vitro Pgp-mediated efflux for a series of PDE9 inhibitors

AU - Fjelbye, Kasper

AU - Marigo, Mauro

AU - Clausen, Rasmus P.

AU - Jørgensen, Erling B.

AU - Christoffersen, Claus T.

AU - Juhl, Karsten

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1039/c8md00114f

DO - 10.1039/c8md00114f

M3 - Journal article

C2 - 30108979

AN - SCOPUS:85047490657

SN - 2040-2503

VL - 9

SP - 893

EP - 896

JO - MedChemComm

JF - MedChemComm

IS - 5

ER -

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

Abstract

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