Structure-activity relationship studies and sleep-promoting activity of novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 2

  • Bioorg Med Chem Lett. 2013 Jul 1;23(13):3857-63. doi: 10.1016/j.bmcl.2013.04.071.
Thierry Sifferlen  1 ,  Ralf Koberstein ,  Emmanuelle Cottreel ,  Amandine Boller ,  Thomas Weller ,  John Gatfield ,  Catherine Brisbare-Roch ,  Francois Jenck ,  Christoph Boss
Affiliations
  • 1. Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
PMID: 23719231 DOI: 10.1016/j.bmcl.2013.04.071
Abstract

Replacement of the dimethoxyphenyl moiety in the core skeleton of almorexant by appropriately substituted imidazoles afforded novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as potent dual orexin receptor antagonists. We describe in this Letter our efforts to further optimize the potency and brain penetration of these derivatives by fine-tuning of the pivotal phenethyl motif, and we comment on the sleep-promoting activity of selected compounds in a rat electroencephalographic (EEG) model.