학술논문
Kinetic profiling of novel spirobenzo-oxazinepiperidinone derivatives as equilibrative nucleoside transporter 1 inhibitors.
Document Type
Academic Journal
Author
Vlachodimou A; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.; Bouma J; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.; De Cleyn M; Janssen Research and Development, Antwerpseweg 30, 2340, Beerse, Belgium.; Berthelot D; Janssen Research and Development, Antwerpseweg 30, 2340, Beerse, Belgium.; Pype S; Janssen Research and Development, Antwerpseweg 30, 2340, Beerse, Belgium.; Bosmans JP; Janssen Research and Development, Antwerpseweg 30, 2340, Beerse, Belgium.; van Vlijmen H; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.; Janssen Research and Development, Antwerpseweg 30, 2340, Beerse, Belgium.; Wroblowski B; Janssen Research and Development, Antwerpseweg 30, 2340, Beerse, Belgium.; Heitman LH; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.; IJzerman AP; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands. ijzerman@lacdr.leidenuniv.nl.
Source
Publisher: Springer Country of Publication: Netherlands NLM ID: 101250499 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-9546 (Electronic) Linking ISSN: 15739538 NLM ISO Abbreviation: Purinergic Signal Subsets: MEDLINE
Subject
Language
English
Abstract
Evaluation of kinetic parameters of drug-target binding, k on , k off , and residence time (RT), in addition to the traditional in vitro parameter of affinity is receiving increasing attention in the early stages of drug discovery. Target binding kinetics emerges as a meaningful concept for the evaluation of a ligand's duration of action and more generally drug efficacy and safety. We report the biological evaluation of a novel series of spirobenzo-oxazinepiperidinone derivatives as inhibitors of the human equilibrative nucleoside transporter 1 (hENT1, SLC29A1). The compounds were evaluated in radioligand binding experiments, i.e., displacement, competition association, and washout assays, to evaluate their affinity and binding kinetic parameters. We also linked these pharmacological parameters to the compounds' chemical characteristics, and learned that separate moieties of the molecules governed target affinity and binding kinetics. Among the 29 compounds tested, 28 stood out with high affinity and a long residence time of 87 min. These findings reveal the importance of supplementing affinity data with binding kinetics at transport proteins such as hENT1.
(© 2023. The Author(s).)
(© 2023. The Author(s).)