The discovery and structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles as selective, CNS penetrating H1-antihistamines for insomnia

  • Bioorg Med Chem Lett. 2010 May 1;20(9):2916-9. doi: 10.1016/j.bmcl.2010.03.027.
Karine Lavrador-Erb  1 ,  Satheesh Babu Ravula ,  Jinghua Yu ,  Said Zamani-Kord ,  Wilna J Moree ,  Robert E Petroski ,  Jianyun Wen ,  Siobhan Malany ,  Samuel R J Hoare ,  Ajay Madan ,  Paul D Crowe ,  Graham Beaton
Affiliations
  • 1. Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA.
PMID: 20347297 DOI: 10.1016/j.bmcl.2010.03.027
Abstract

A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.

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