title: Novel benzothiophene H1-antihistamines for the treatment of insomnia.
abstract: SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
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: Florence
authors.initials: F
authors.lastname: Jovic
authors.forename: Timothy
authors.initials: T
authors.lastname: Coon
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Bin-Feng
authors.initials: BF
authors.lastname: Li
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
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: Zhihong
authors.initials: Z
authors.lastname: O'Brien
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: 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: D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D011969:Receptors, Histamine H1 / Q000378:metabolism; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D013876:Thiophenes; C088015:benzothiophene