Discovery of dihydropyrazino-benzimidazole derivatives as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs)

  • Eur J Med Chem. 2020 Jan 15;186:111881. doi: 10.1016/j.ejmech.2019.111881.
György Szabó  1 ,  Sándor Kolok  2 ,  Zoltán Orgován  3 ,  Mónika Vastag  2 ,  Zoltán Béni  2 ,  János Kóti  2 ,  Katalin Sághy  2 ,  György I Lévay  2 ,  István Greiner  2 ,  György M Keserű  4
Affiliations
  • 1. Gedeon Richter Plc., 19-21 Gyömrői út, Budapest, 1103, Hungary. Electronic address: [email protected].
  • 2. Gedeon Richter Plc., 19-21 Gyömrői út, Budapest, 1103, Hungary.
  • 3. Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 2 Magyar tudósok körútja, Budapest, 1117, Hungary.
  • 4. Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 2 Magyar tudósok körútja, Budapest, 1117, Hungary. Electronic address: [email protected].
PMID: 31780081 DOI: 10.1016/j.ejmech.2019.111881
Abstract

A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure-activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies.

Keywords
Dihydropyrazino-benzimidazoles; Pharmacophore based optimization; Positive allosteric modulator; Scaffold hopping; mGlu(2) receptor.
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