title: Structure-Affinity Relationships (SARs) and Structure-Kinetics Relationships (SKRs) of Kv11.1 Blockers.
abstract: Kv11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent pro-arrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of Kv11.1 blockers next to their structure-affinity relationships. We learned that despite dramatic differences in affinities and association rates, there were hardly any variations in the dissociation rate constants of these molecules with residence times (RTs) of a few minutes only. Hence, we synthesized 16 novel molecules, in particular in the pyridinium class of compounds, to further address this peculiar phenomenon. We found molecules with very short RTs (e.g., 0.34 min for 37) and much longer RTs (e.g., 105 min for 38). This enabled us to construct a k on-k off-KD kinetic map for all compounds and subsequently divide the map into four provisional quadrants, providing a possible framework for a further and more precise categorization of Kv11.1 blockers. Additionally, two representative compounds (21 and 38) were tested in patch clamp assays, and their RTs were linked to their functional IC50 values. Our findings strongly suggest the importance of the simultaneous study of ligand affinities and kinetic parameters, which may help to explain and predict Kv11.1-mediated cardiotoxicity.
authors.affiliation: †Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yu
authors.affiliation: †Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Jacobus P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.affiliation: †Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Julien
authors.initials: J
authors.lastname: Louvel
authors.affiliation: †Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: 't Hart
authors.forename: Martin B
authors.initials: MB
authors.lastname: Rook
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.affiliation: †Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.affiliation: †Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers