Route to prolonged residence time at the histamine H1 receptor: Growing from desloratadine to rupatadine

Reggie Bosma, Zhiyong Wang, Albert J. Kooistra, Nick Bushby, Sebastiaan Kuhne, Jelle Van Den Bor, Michael J. Waring, Chris De Graaf, Iwan J. De Esch, Henry F. Vischer, Robert J. Sheppard, Maikel Wijtmans, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)6630-6644
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number14
DOIs
Publication statusPublished - 25 Jul 2019

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Histamine H1 Receptors
Pharmaceutical Preparations
Amines
Ligands
rupatadine
desloratadine

Cite this

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title = "Route to prolonged residence time at the histamine H1 receptor: Growing from desloratadine to rupatadine",
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.",
author = "Reggie Bosma and Zhiyong Wang and Kooistra, {Albert J.} and Nick Bushby and Sebastiaan Kuhne and {Van Den Bor}, Jelle and Waring, {Michael J.} and {De Graaf}, Chris and {De Esch}, {Iwan J.} and Vischer, {Henry F.} and Sheppard, {Robert J.} and Maikel Wijtmans and Rob Leurs",
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month = "7",
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doi = "10.1021/acs.jmedchem.9b00447",
language = "English",
volume = "62",
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journal = "Journal of Medicinal Chemistry",
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publisher = "American Chemical Society",
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Route to prolonged residence time at the histamine H1 receptor : Growing from desloratadine to rupatadine. / Bosma, Reggie; Wang, Zhiyong; Kooistra, Albert J.; Bushby, Nick; Kuhne, Sebastiaan; Van Den Bor, Jelle; Waring, Michael J.; De Graaf, Chris; De Esch, Iwan J.; Vischer, Henry F.; Sheppard, Robert J.; Wijtmans, Maikel; Leurs, Rob.

In: Journal of Medicinal Chemistry, Vol. 62, No. 14, 25.07.2019, p. 6630-6644.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Route to prolonged residence time at the histamine H1 receptor

T2 - Growing from desloratadine to rupatadine

AU - Bosma, Reggie

AU - Wang, Zhiyong

AU - Kooistra, Albert J.

AU - Bushby, Nick

AU - Kuhne, Sebastiaan

AU - Van Den Bor, Jelle

AU - Waring, Michael J.

AU - De Graaf, Chris

AU - De Esch, Iwan J.

AU - Vischer, Henry F.

AU - Sheppard, Robert J.

AU - Wijtmans, Maikel

AU - Leurs, Rob

PY - 2019/7/25

Y1 - 2019/7/25

N2 - 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.

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