189045-24-7Relevant academic research and scientific papers
Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor-2 Positive Allosteric Modulators against Migraine
Szabó, Gy?rgy,Erdélyi, Péter,Kolok, Sándor,Vastag, Mónika,Halász, Attila S.,Kis-Varga, Istvánné,Lévay, Gy?rgy I.,Béni, Zoltán,Kóti, János,Greiner, István,Keser?, Gy?rgy M.
, p. 8607 - 8620 (2021)
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, compound34showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.
