The multiobjective based design, synthesis and evaluation of the arylsulfonamide/amide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines as a novel class of potent 5-HT7 receptor antagonists

An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds 24–95 were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT7R. Additionally, the targeted library members were tested for 5-HT1A, 5-HT6, and D2 receptors. Selected compounds of particular interest were examined for their intrinsic activity at 5-HT7R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT7R ligand (Ki = 0.3 nM) with strong antagonistic properties (Kb = 1 nM) and a 1450-fold selectivity over 5-HT1ARs.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel arylsulfonamide derivatives of acyclic amines as 5-HT7 antagonists were developed. ► Concept of flexible biomimetics of classic long-chain arylpiperazines was presented. ► Virtual combinatorial library and multistep virtual screening for compound selection was described. ► 72 member library was synthesized using solid-phase synthesis method.