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

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

Affiliations

  • 1 Gedeon Richter Plc., 19-21 Gyömrői út, Budapest, 1103, Hungary. Electronic address: gy.szabo@richter.hu.
  • 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: keseru.gyorgy@ttk.hu.
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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