Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia.
Analogues of the known H(1)-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.
Moree
Wilna J
WJ
Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA.
Li
Bin-Feng
BF
Jovic
Florence
F
Coon
Timothy
T
Yu
Jinghua
J
Gross
Raymond S
RS
Tucci
Fabio
F
Marinkovic
Dragan
D
Zamani-Kord
Said
S
Malany
Siobhan
S
Bradbury
Margaret J
MJ
Hernandez
Lisa M
LM
O'Brien
Zhihong
Z
Wen
Jianyun
J
Wang
Hua
H
Hoare
Samuel R J
SR
Petroski
Robert E
RE
Sacaan
Aida
A
Madan
Ajay
A
Crowe
Paul D
PD
Beaton
Graham
G
D000818:Animals; D001921:Brain / Q000378:metabolism; D004115:Dimethindene / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004569:Electroencephalography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013379:Substrate Specificity
D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D011976:Receptors, Muscarinic; D004115:Dimethindene