Novel benzothiophene H1-antihistamines for the treatment of insomnia

SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H1-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.

Graphical abstractStructure–activity relationships around the lead H1-antihistamine 2, a potential agent for the treatment of insomnia, led to the identification of several potential backups with differences in projected pharmacokinetic profiles. While human PK of 16d indicated a suitable half-life, the compound was not moved into development due to significant variability in pharmacokinetic profile. From preclinical studies, compound 28b may represent a more suitable backup.Figure optionsDownload full-size imageDownload as PowerPoint slide