Brain-penetrating 2-aminobenzimidazole H1-antihistamines for the treatment of insomnia

The benzimidazole core of the selective non-brain-penetrating H₁-antihistamine mizolastine was used to identify a series of brain-penetrating H₁-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H₁-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.