Structure–Affinity Relationships (SARs) and Structure–Kinetics Relationships (SKRs) of K_v11.1 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.

A binding kinetics study of human adenosine A3 receptor agonists

“…3C and 3D). Such correlation between affinity and on-rates has been reported in the case of other GPCRs [40] and ion channels [41, 42]. However, in the current study, variations in association rate constants were approximately 10-fold (logk on : 5.0 to 6.0), much smaller than at the other targets mentioned above.…”

Structure–Affinity Relationships and Structure–Kinetics Relationships of Pyrido[2,1-f]purine-2,4-dione Derivatives as Human Adenosine A3 Receptor Antagonists

“…In previous studies, such a separation has explained the different therapeutic effects molecules exhibit highlighting the benefits of such an in-depth analysis. 35 , 36 …”

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

“…Characterization of the drug-target complex lifetime or RT in early phases of the drug discovery and development process might help to improve the prediction of in vivo efficacy and safety 12–15 . Evidence from retrospective studies has shown that several marketed drugs exhibit a long RT on their target 13, 29 , prompting the prospective optimization of both affinity and kinetic properties of compounds for a variety of targets 17, 25, 30–32 . In this regard, 15a was discovered by optimizing a reported lead in the development of MK-0812, a Merck CCR2 antagonist that has failed in clinical trials due to lack of efficacy 33 .…”