Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists.

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.