Bioorganic & Medicinal Chemistry Letters 2009-08-01

Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia.

Timothy Coon, Wilna J Moree, Binfeng Li, Jinghua Yu, Said Zamani-Kord, Siobhan Malany, Mark A Santos, Lisa M Hernandez, Robert E Petroski, Aixia Sun, Jenny Wen, Sue Sullivan, Jason Haelewyn, Michael Hedrick, Samuel J Hoare, Margaret J Bradbury, Paul D Crowe, Graham Beaton

Index: Bioorg. Med. Chem. Lett. 19(15) , 4380-4, (2009)

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Abstract

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.