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

2009; Elsevier BV; Volume: 19; Issue: 15 Linguagem: Inglês

10.1016/j.bmcl.2009.05.086

1464-3405

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

Asthma and respiratory diseases

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.