Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor-2 Positive Allosteric Modulators against Migraine.
J Med Chem
; 64(12): 8607-8620, 2021 06 24.
Article
in En
| MEDLINE
| ID: mdl-34080424
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazines
/
Benzimidazoles
/
Receptors, Metabotropic Glutamate
/
Excitatory Amino Acid Agonists
/
Migraine Disorders
Limits:
Animals
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2021
Document type:
Article
Affiliation country: