title: Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia.
abstract: 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.
authors: Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA.
authors: Timothy
authors: T
authors: Coon
authors: Wilna J
authors: WJ
authors: Moree
authors: Binfeng
authors: B
authors: Li
authors: Jinghua
authors: J
authors: Yu
authors: Said
authors: S
authors: Zamani-Kord
authors: Siobhan
authors: S
authors: Malany
authors: Mark A
authors: MA
authors: Santos
authors: Lisa M
authors: LM
authors: Hernandez
authors: Robert E
authors: RE
authors: Petroski
authors: Aixia
authors: A
authors: Sun
authors: Jenny
authors: J
authors: Wen
authors: Sue
authors: S
authors: Sullivan
authors: Jason
authors: J
authors: Haelewyn
authors: Michael
authors: M
authors: Hedrick
authors: Samuel J
authors: SJ
authors: Hoare
authors: Margaret J
authors: MJ
authors: Bradbury
authors: Paul D
authors: PD
authors: Crowe
authors: Graham
authors: G
authors: Beaton
mesh_terms: 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
chemical_list: D001562:Benzimidazoles; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006633:Histamine Antagonists; C000606913:KCNH2 protein, human; C027391:2-aminobenzimidazole