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

  • Bioorg Med Chem Lett. 2009 Aug 1;19(15):4380-4. doi: 10.1016/j.bmcl.2009.05.086.
Timothy Coon  1 ,  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
Affiliations
  • 1. Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA.
PMID: 19553115 DOI: 10.1016/j.bmcl.2009.05.086
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.