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

Abstract

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.

Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor-2 Positive Allosteric Modulators against Migraine

“…Alignment of the available pharmacophores revealed that the N-acceptor feature of the benzimidazole ring was replaced by carbonyl oxygen in the dihydropyrazino-benzimidazolone system (Figure A). Pharmacophore alignment of benzotriazole chemotypes including an optimized Merck compound ( 15 ), our advanced lead ( 13 ), and the optimized fragment ( 14 ) suggested that in addition to the N-acceptor feature, a partial negative charge is preferred (Figure B).…”

“…In order to develop powerful tools for translational mGluR2 research, we followed a fragment-based optimization strategy. In our previous work, we demonstrated that the optimization of a fragment size hit to a large lead ( 13 ) was less fruitful than a fragment optimization strategy which yielded 14 , a potent mGluR2 PAM fragment reported for the first time (Figure ). Results achieved in the absence of structural information prompted us to extend this approach for the dihydropyrazino-benzimidazolone core.…”

Allosteric Molecular Switches in Metabotropic Glutamate Receptors

“…SIB1893 [117] appeared to be an mGlu 5 NAM; however, TCN238 [118] turned to be an mGlu 4 PAM. In addition, VU0418506 [119] and its close analogue 1‐benzyl‐1 H ‐1,2,3‐benzotriazole ( 57 ) [120] were reported as optimized mGlu 4 selective PAM and as a HTS hit for mGlu 2 , respectively. Pittolo and co‐workers described a potent mGlu 5 NAM ( 58 ) [121] during the development of photoisomerizable ligands from an mGlu 4 PAM VU0415374 [122] .…”

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

“…A recent example of fragment optimization using only chemical optimization in the absence of a crystal structure was reported by Szabó et al (2018). The researchers identified a fragment-like hit in a functional assay looking for positive allosteric modulators of metabotropic glutamate receptor 2.…”