title: Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines.
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.
authors.affiliation: Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. fjanssen@prdbe.jnj.com
authors.forename: Frans
authors.initials: F
authors.lastname: Janssens
authors.forename: Jos
authors.initials: J
authors.lastname: Leenaerts
authors.forename: Gaston
authors.initials: G
authors.lastname: Diels
authors.forename: Benoît
authors.initials: B
authors.lastname: De Boeck
authors.forename: Anton
authors.initials: A
authors.lastname: Megens
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Koen
authors.initials: K
authors.lastname: van Rossem
authors.forename: Johan
authors.initials: J
authors.lastname: Beetens
authors.forename: Marcel
authors.initials: M
authors.lastname: Borgers
mesh_terms: D000707:Anaphylaxis / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003872:Dermatitis / Q000188:drug therapy / Q000276:immunology; D003879:Dermatologic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D004355:Drug Stability; D005260:Female; D006168:Guinea Pigs; D039563:Histamine H1 Antagonists, Non-Sedating / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D008297:Male; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D016276:Ventricular Function / Q000187:drug effects
chemical_list: C500082:5,6-dihydrospiro(11H-imidazo(2,1-b)(3)benzazepine-11,4'-piperidine)-3-carboxamide; D001552:Benzazepines; D003879:Dermatologic Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D007093:Imidazoles; D010880:Piperidines; D013141:Spiro Compounds