jm201079g_si_001.pdf (130.86 kB)
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
journal contribution
posted on 2011-12-08, 00:00 authored by Alexandre
V. Ivachtchenko, Elena S. Golovina, Madina G. Kadieva, Volodymyr M. Kysil, Oleg D. Mitkin, Sergey E. Tkachenko, Ilya M. OkunSyntheses, biological evaluation as 5-HT6 receptor
(5-HT6R) 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-HT6R. 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 5HT6R 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 5HT6R 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.