Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists.


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.

DOI: 10.1016/j.bmcl.2010.01.070

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@article{Sifferlen2010NovelPA, title={Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists.}, author={Thierry Sifferlen and Christoph Boss and Emmanuelle Cottreel and Ralf Koberstein and Markus Gude and Hamed Aissaoui and Thomas Weller and John Gatfield and Catherine Brisbare-Roch and François Jenck}, journal={Bioorganic & medicinal chemistry letters}, year={2010}, volume={20 5}, pages={1539-42} }