posted on 2024-03-01, 12:34authored byBalázs Krámos, Zsuzsa Hadady, Attila Makó, Gábor Szántó, Nóra Felföldi, Ildikó Magdó, Amrita Ágnes Bobok, Imre Bata, Viktor Román, András Visegrády, György
M. Keserű, István Greiner, János Éles
Selecting
a known HTS hit with the pyrazolo[1,5-a]pyrimidine
core, our project was started from CMPPE, and its optimization
was driven by a ligand-based pharmacophore model developed on the
basis of published GABAB positive allosteric modulators
(PAMs). Our primary goal was to improve the potency by finding new
enthalpic interactions. Therefore, we included the lipophilic ligand
efficiency (LLE or LipE) as an objective function in the optimization
that led to a carboxylic acid derivative (34). This lead
candidate offers the possibility to improve potency without drastically
inflating the physicochemical properties. Although the discovery of
the novel carboxyl feature was surprising, it turned out to be an
important element of the GABAB PAM pharmacophore that can
be perfectly explained based on the new protein structures. Rationalizing
the binding mode of 34, we analyzed the intersubunit
PAM binding site of GABAB receptor using the publicly available
experimental structures.