Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines

Frans Janssens; Jos Leenaerts; Gaston Diels; Benoît De Boeck; Anton Megens; Xavier Langlois; Koen van Rossem; Johan Beetens; Marcel Borgers

doi:10.1021/jm049495j

Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines

J Med Chem. 2005 Mar 24;48(6):2154-66. doi: 10.1021/jm049495j.

Authors

Frans Janssens¹, Jos Leenaerts, Gaston Diels, Benoît De Boeck, Anton Megens, Xavier Langlois, Koen van Rossem, Johan Beetens, Marcel Borgers

Affiliation

¹ Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. fjanssen@prdbe.jnj.com

PMID: 15771458
DOI: 10.1021/jm049495j

Abstract

Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.

MeSH terms

Anaphylaxis / chemically induced
Anaphylaxis / drug therapy
Animals
Arrhythmias, Cardiac / chemically induced
Benzazepines / chemical synthesis*
Benzazepines / pharmacology
Benzazepines / toxicity
Blood-Brain Barrier / metabolism
CHO Cells
Cricetinae
Cricetulus
Dermatitis / drug therapy
Dermatitis / immunology
Dermatologic Agents / chemical synthesis*
Dermatologic Agents / pharmacology
Dermatologic Agents / toxicity
Dogs
Drug Stability
Female
Guinea Pigs
Histamine H1 Antagonists, Non-Sedating / chemical synthesis*
Histamine H1 Antagonists, Non-Sedating / pharmacology
Histamine H1 Antagonists, Non-Sedating / toxicity
Hydrogen-Ion Concentration
Imidazoles / chemical synthesis*
Imidazoles / pharmacology
Imidazoles / toxicity
In Vitro Techniques
Male
Passive Cutaneous Anaphylaxis / drug effects
Piperidines / chemical synthesis*
Piperidines / pharmacology
Piperidines / toxicity
Radioligand Assay
Rats
Rats, Wistar
Solubility
Spiro Compounds / chemical synthesis*
Spiro Compounds / pharmacology
Spiro Compounds / toxicity
Structure-Activity Relationship
Ventricular Function / drug effects

Substances

5,6-dihydrospiro(11H-imidazo(2,1-b)(3)benzazepine-11,4'-piperidine)-3-carboxamide
Benzazepines
Dermatologic Agents
Histamine H1 Antagonists, Non-Sedating
Imidazoles
Piperidines
Spiro Compounds