Coon T, Moree WJ, Li B, Yu J, Zamani-Kord S, Malany S, Santos MA, Hernandez LM, Petroski RE, Sun A, Wen J, Sullivan S, Haelewyn J, Hedrick M, Hoare SJ, Bradbury MJ, Crowe PD, Beaton G
Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia. [JOURNAL ARTICLE]
Bioorg Med Chem Lett 2009 May 27.
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.
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