triprolidine and Sleep-Initiation-and-Maintenance-Disorders

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.

Topics: Animals; Benzimidazoles; Brain; Chemistry, Pharmaceutical; Drug Design; Electroencephalography; Electromyography; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Histamine Antagonists; Humans; Models, Chemical; Rats; Rats, Sprague-Dawley; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship