Synthesis, structure-activity relationship studies, and identification of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 1

Thierry Sifferlen; Ralf Koberstein; Emmanuelle Cottreel; Amandine Boller; Thomas Weller; John Gatfield; Catherine Brisbare-Roch; Francois Jenck; Christoph Boss

doi:10.1016/j.bmcl.2013.01.088

Synthesis, structure-activity relationship studies, and identification of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 1

Bioorg Med Chem Lett. 2013 Apr 1;23(7):2212-6. doi: 10.1016/j.bmcl.2013.01.088. Epub 2013 Jan 29.

Authors

Thierry Sifferlen¹, Ralf Koberstein, Emmanuelle Cottreel, Amandine Boller, Thomas Weller, John Gatfield, Catherine Brisbare-Roch, Francois Jenck, Christoph Boss

Affiliation

¹ Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.

PMID: 23434414
DOI: 10.1016/j.bmcl.2013.01.088

Abstract

A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication.

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Structure
Orexin Receptors
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacology*
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, Neuropeptide / antagonists & inhibitors*
Structure-Activity Relationship

Substances

HCRTR2 protein, human
Orexin Receptors
Pyrazines
Receptors, G-Protein-Coupled
Receptors, Neuropeptide