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.