Synthesis and Structure–Activity Relationship (SAR) of (5,7-Disubstituted 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamines as Potent Serotonin 5-HT₆ Receptor (5-HT₆R) Antagonists

Abstract

Syntheses, biological evaluation as 5-HT(6) receptor (5-HT(6)R) antagonists, and structure-activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT(6)R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT(6)R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT(6)R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor.

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6receptor antagonists and beyond

“…Attempts to replace this functional group with other fragments in most cases decreased the binding affinity to the receptor. 4,[8][9][10][11]30,31 Despite considering the HBA functionality of the sulfonyl group, its full impact on 5-HT 6 R ligand activity is still unclear.…”

“…Sulfones and sulfonamides are the most widely represented classes of the serotonin receptor subtype 6 (5-HT 6 R) ligands [8][9][10][11][12][13] (87.8% (1817) of the total number (2069) of recognized 5-HT 6 R ligands with inhibition constants K i (or IC 50 /2) 14 # 100 nM; ChEMBL database; 15 ver. 23).…”

Crystal structure of N-(5-((3,5-dimethylisoxazol-4-yl)sulfonyl)quinolin-8-yl)benzamide, C21H17N3O4S

“…Heteroaromatic sulfones are important organic intermediates and play a vital role in many elds such as pharmacy, and biology [1,2]. Antimicrobial activity and antioxidant activity of arylsulfonyl isoxazoles have been reported [3,4].…”

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

“…During this decade or so, there was a plenty of chemistry developed around different nuclei including the indole-based ones or even much simpler biphenyl sulfones and sulfonamides [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]34 ( Figure 2). Suven has reported several series of 1-sulfonylindoles bearing the amino group at 3 or 4 or 5 position of the central core [31][32][33] .…”