(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT₆ Receptor

Abstract

5-HT(6) receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT(6) receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT(6) receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT(2B) receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.

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

“…[23][24][25][26][27][28] In the pharmacophore model of the 5-HT 6 R antagonists, the sulfonyl fragment is usually considered as the strong hydrogen bond acceptor. [23][24][25]27,28 Based on docking study, it is postulated that it interacts with N6.55 and S5. 43 forming O-H/O and N-H/O bonds, 23,27,28 respectively.…”

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] .…”

Fingerprint-based consensus virtual screening towards structurally new 5-HT6R ligands

“…Though several reports have proven that the presence of a basic nitrogen atom enabling formation of the interaction of its protonated form and D3.32 is not indispensable for 5-HT 6 R anchoring [56][57][58][59][60] , the fraction of nonbasic compounds within known 5-HT 6 R ligands is low (~7% within the set of active compounds included in the training set). The majority of 5-HT 6 R ligands keep fitting the standard pharmacophore model, 61,62 which requires the possession of a positive ionizable group.…”