Novel benzothiophene H1-antihistamines for the treatment of insomnia

  • Bioorg Med Chem Lett. 2010 Apr 1;20(7):2316-20. doi: 10.1016/j.bmcl.2010.01.134.
Wilna J Moree  1 ,  Florence Jovic ,  Timothy Coon ,  Jinghua Yu ,  Bin-Feng Li ,  Fabio C Tucci ,  Dragan Marinkovic ,  Raymond S Gross ,  Siobhan Malany ,  Margaret J Bradbury ,  Lisa M Hernandez ,  Zhihong O'Brien ,  Jianyun Wen ,  Hua Wang ,  Samuel R J Hoare ,  Robert E Petroski ,  Aida Sacaan ,  Ajay Madan ,  Paul D Crowe ,  Graham Beaton
Affiliations
  • 1. Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. [email protected]
PMID: 20188547 DOI: 10.1016/j.bmcl.2010.01.134
Abstract

SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.