title: Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia.
abstract: Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
authors.affiliation: Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. wilna.moree@gmail.com
authors.forename: Wilna J
authors.initials: WJ
authors.lastname: Moree
authors.forename: Bin-Feng
authors.initials: BF
authors.lastname: Li
authors.forename: Said
authors.initials: S
authors.lastname: Zamani-Kord
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Timothy
authors.initials: T
authors.lastname: Coon
authors.forename: Charles
authors.initials: C
authors.lastname: Huang
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Bradbury
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hernandez
authors.forename: Jianyun
authors.initials: J
authors.lastname: Wen
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Samuel R J
authors.initials: SR
authors.lastname: Hoare
authors.forename: Robert E
authors.initials: RE
authors.lastname: Petroski
authors.forename: Kayvon
authors.initials: K
authors.lastname: Jalali
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Aida
authors.initials: A
authors.lastname: Sacaan
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: Graham
authors.initials: G
authors.lastname: Beaton
mesh_terms: D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004115:Dimethindene / Q000737:chemistry; D004569:Electroencephalography; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007192:Indenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000378:metabolism; D023421:Models, Animal; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D006634:Histamine H1 Antagonists; D007192:Indenes; D011724:Pyridazines; D011969:Receptors, Histamine H1; D004115:Dimethindene; C093581:indene; D019389:Cytochrome P-450 CYP2D6