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

Our previous scaffold-hopping attempts
resulted in dihydropyrazino-benzimidazoles
as metabotropic glutamate receptor-2 (mGluR2) positive allosteric
modulators (PAMs) with suboptimal drug-like profiles. Here, we report
an alternative fragment-based optimization strategy applied on the
new dihydropyrazino-benzimidazolone scaffold. Analyzing published
high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach
to identify suitable growing vectors and optimize the scaffold in
these directions. This strategy resulted in a new fragment like lead
(34) with improved druglike properties that were translated
to sufficient pharmacokinetics and validated proof-of-concept studies
in migraine. Gratifyingly, compound 34 showed reasonable
activity in the partial infraorbital nerve ligation, a migraine disease
model that might open this indication for mGluR2 PAMs.