2. Academic Validation
  3. Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists

Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists

  • Bioorg Med Chem Lett. 2010 Mar 1;20(5):1539-42. doi: 10.1016/j.bmcl.2010.01.070.
Thierry Sifferlen 1,  Christoph Boss,  Emmanuelle Cottreel,  Ralf Koberstein,  Markus Gude,  Hamed Aissaoui,  Thomas Weller,  John Gatfield,  Catherine Brisbare-Roch,  Francois Jenck
Affiliations

Affiliation

  • 1 Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. [email protected]
PMID: 20144866 DOI: 10.1016/j.bmcl.2010.01.070
Abstract

A novel series of dual orexin receptor antagonists was prepared by heteroaromatic five-membered ring system replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Thus, replacement of the dimethoxyphenyl by a substituted pyrazole and additional optimization of the substitution pattern of the phenethyl motif allowed the identification of potent antagonists with low nanomolar affinity for hOX(1)R and hOX(2)R. The synthesis and structure-activity relationship of these novel antagonists will be discussed in this communication. These investigations furnished several suitable candidates for further evaluation in in vivo studies in rats.

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