Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia

Analogs of the known H1-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.

Several indenes with high affinity for the H1 receptor and appropriate selectivity versus off-targets were assessed for metabolism profile and in vivo properties. Compound 10a displayed a diversified metabolism profile, 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.Figure optionsDownload as PowerPoint slide