Propafenone analogue with additional H‐bond acceptor group shows increased inhibitory activity on P‐glycoprotein

Author(s)

Anna Cseke, Theresa Schwarz, Sankalp Jain, Simon Decker, Kerstin Vogl, Ernst Urban, Gerhard Ecker

Abstract

P‐glycoprotein (P‐gp) is an ATP‐dependent efflux pump that has a marked impact on the absorption, distribution, and excretion of therapeutic drugs. As P‐gp inhibition can result in drug–drug interactions and altered drug bioavailability, identifying molecular properties that are linked to inhibition is of great interest in drug development. In this study, we combined chemical synthesis, in vitro testing, quantitative structure–activity relationship analysis, and docking studies to investigate the role of hydrogen bond (H‐bond) donor/acceptor properties in transporter–ligand interaction. In a previous work, it has been shown that propafenone analogs with a 4‐hydroxy‐4‐piperidine moiety exhibit a generally 10‐fold higher P‐gp inhibitory activity than expected based on their lipophilicity. Here, we specifically expanded the data set by introducing substituents at position 4 of the 4‐phenylpiperidine moiety to assess the importance of H‐bond donor/acceptor features in this region. The results suggest that indeed an H‐bond acceptor, such as hydroxy and methoxy, increases the affinity by forming a H‐bond with Tyr310.

Organisation(s)

External organisation(s)

National Institutes of Health (NIH)

Journal

Archiv der Pharmazie

Volume

353

No. of pages

11

ISSN

0365-6233

DOI

https://doi.org/10.1002/ardp.201900269

Publication date

03-2020

Peer reviewed

Yes

Austrian Fields of Science 2012

104015 Organic chemistry, 102004 Bioinformatics, 106002 Biochemistry, 301207 Pharmaceutical chemistry

Keywords

ASJC Scopus subject areas

Drug Discovery, Pharmaceutical Science

Portal url

https://ucrisportal.univie.ac.at/en/publications/propafenone-analogue-with-additional-hbond-acceptor-group-shows-increased-inhibitory-activity-on-pglycoprotein(f6b85fdc-9ed8-41cb-bcee-2dc628b50bae).html