Abstract
Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine (1) and desloratadine (2) have a long residence time at the histamine H1 receptor (H1R). Through development of a [3H]levocetirizine radiolabel, we find that the residence time of 1 exceeds that of 2 more than 10-fold. This was further explored with 22 synthesized rupatadine and desloratadine analogues. Methylene-linked cycloaliphatic or β-branched substitutions of desloratadine increase the residence time at the H1R, conveying a longer duration of receptor antagonism. However, cycloaliphatic substituents directly attached to the piperidine amine (i.e., lacking the spacer) have decreased binding affinity and residence time compared to their methylene-linked structural analogues. Guided by docking studies, steric constraints within the binding pocket are hypothesized to explain the observed differences in affinity and binding kinetics between analogues.
Original language | English |
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Pages (from-to) | 6630-6644 |
Number of pages | 15 |
Journal | Journal of Medicinal Chemistry |
Volume | 62 |
Issue number | 14 |
DOIs | |
Publication status | Published - 25 Jul 2019 |
Funding
Hans Custers is thanked for technical assistance. This research was financially supported by the EU/EFPIA Innovative Medicines Initiative (IMI) Joint Undertaking, K4DD (grant no. 115366) as well as by the China Scholarship Council (CSC) (grant no. 201506270163).
Funders | Funder number |
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EU/EFPIA Innovative Medicines Initiative | |
Seventh Framework Programme | 115366 |
China Scholarship Council | 201506270163 |
Innovative Medicines Initiative |