Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia.
The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.
Coon
Timothy
T
Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA.
Moree
Wilna J
WJ
Li
Binfeng
B
Yu
Jinghua
J
Zamani-Kord
Said
S
Malany
Siobhan
S
Santos
Mark A
MA
Hernandez
Lisa M
LM
Petroski
Robert E
RE
Sun
Aixia
A
Wen
Jenny
J
Sullivan
Sue
S
Haelewyn
Jason
J
Hedrick
Michael
M
Hoare
Samuel J
SJ
Bradbury
Margaret J
MJ
Crowe
Paul D
PD
Beaton
Graham
G
D000818:Animals; D001562:Benzimidazoles / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001921:Brain / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D051381:Rats; D017207:Rats, Sprague-Dawley; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006633:Histamine Antagonists; C000606913:KCNH2 protein, human; C027391:2-aminobenzimidazole