Synthesis of cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines and their evaluation as 5-HT6 receptor antagonists

Synthesis and biological evaluation of 1 (‘angular’) and 2 (‘linear’) сycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines as novel ligands of the 5-HT6 receptors are disclosed. The new compounds 1 and 2 are highly selective antagonists of the receptor with sub-nanomolar affinities (Ki <1 nM). In its structure, this new chemotype lacks a basic ionizable side chain, which is considered as the characteristic feature of the 5-HT6 receptor antagonists pharmacophore model.

Graphical abstractWe synthesized and investigated the cycloalkane-annelated 3-phenyl-pyrazolo[1,5-a]pyrimidine systems, 1 and 2, as a novel scaffold for the development of highly selective and potent antagonists of the 5-HT6 receptors.Figure optionsDownload full-size imageDownload as PowerPoint slide