10.1021/jm201079g.s001 Alexandre V. Ivachtchenko Alexandre V. Ivachtchenko Elena S. Golovina Elena S. Golovina Madina G. Kadieva Madina G. Kadieva Volodymyr M. Kysil Volodymyr M. Kysil Oleg D. Mitkin Oleg D. Mitkin Sergey E. Tkachenko Sergey E. Tkachenko Ilya M. Okun Ilya M. Okun Synthesis and Structure–Activity Relationship (SAR) of (5,7-Disubstituted 3-phenylsulfonyl-pyrazolo[1,5-<i>a</i>]pyrimidin-2-yl)-methylamines as Potent Serotonin 5-HT<sub>6</sub> Receptor (5-HT<sub>6</sub>R) Antagonists American Chemical Society 2011 cLogP values PI group SAR gyration radii 5 HT 6R 5 HT 6R ligands ADME characteristics receptor HEK pyrimidine ring scaffold members intramolecular hydrogen bond potency molecule size ionizable group 2011-12-08 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Synthesis_and_Structure_Activity_Relationship_SAR_of_5_7_Disubstituted_3_phenylsulfonyl_pyrazolo_1_5_i_a_i_pyrimidin_2_yl_methylamines_as_Potent_Serotonin_5_HT_sub_6_sub_Receptor_5_HT_sub_6_sub_R_Antagonists/2573725 Syntheses, biological evaluation as 5-HT<sub>6</sub> receptor (5-HT<sub>6</sub>R) antagonists, and structure–activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo­[1,5-<i>a</i>]­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<sub>6</sub>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<sub>6</sub>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<sub>6</sub>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.