Characterization of Novel Selective H1-Antihistamines for Clinical Evaluation in the Treatment of Insomnia

Analogues of the known H1-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-09, Vol.52 (17), p.5307-5310
Hauptverfasser:	Moree, Wilna J, Li, Bin-Feng, Jovic, Florence, Coon, Timothy, Yu, Jinghua, Gross, Raymond S, Tucci, Fabio, Marinkovic, Dragan, Zamani-Kord, Said, Malany, Siobhan, Bradbury, Margaret J, Hernandez, Lisa M, O’Brien, Zhihong, Wen, Jianyun, Wang, Hua, Hoare, Samuel R. J, Petroski, Robert E, Sacaan, Aida, Madan, Ajay, Crowe, Paul D, Beaton, Graham
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Biological and medical sciences Brain - metabolism Dimethindene - metabolism Dimethindene - pharmacokinetics Dimethindene - pharmacology Dimethindene - therapeutic use Electroencephalography - drug effects Ether-A-Go-Go Potassium Channels - antagonists & inhibitors Histamine H1 Antagonists - metabolism Histamine H1 Antagonists - pharmacokinetics Histamine H1 Antagonists - pharmacology Histamine H1 Antagonists - therapeutic use Humans Medical sciences Miscellaneous Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Rats Receptors, Muscarinic - metabolism Sleep - drug effects Sleep Initiation and Maintenance Disorders - drug therapy Substrate Specificity
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Zusammenfassung:	Analogues of the known H1-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm900933k