Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information

Metabotropic glutamate receptor 2
(mGluR2) positive allosteric modulators (PAMs) have been implicated
as potential pharmacotherapy for psychiatric conditions. Screening
our corporate compound deck, we identified a benzotriazole fragment
(4) that was rapidly optimized to a potent and metabolically
stable early lead (16). The highly lipophilic character
of 16, together with its limited solubility, permeability,
and high protein binding, however, did not allow reaching of the proof
of concept in vivo. Since further attempts on the optimization of druglike properties
were unsuccessful, the original hit 4 has been revisited
and was optimized following the principles of fragment based drug
discovery (FBDD). Lacking structural information on the receptor–ligand
complex, we implemented a group efficiency (GE) based strategy and
identified a new fragment like lead (60) with more balanced
profile. Significant improvement achieved on the druglike properties
nominated the compound for in vivo proof of concept studies that revealed
the chemotype being a promising PAM lead targeting mGluR2 receptors.