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

被引：5

作者：

Szabo, Gyorgy ^{[1
]}

Kolok, Sandor ^{[1
]}

Orgovan, Zoltan ^{[2
]}

Vastag, Monika ^{[1
]}

Beni, Zoltan ^{[1
]}

Koti, Janos ^{[1
]}

Saghy, Katalin ^{[1
]}

Levay, Gyorgy I. ^{[1
]}

Greiner, Istvan ^{[1
]}

Keseru, Gyorgy M. ^{[2
]}

机构：

[1] Gedeon Richter Plc, 19-21 Gyomroi Ut, H-1103 Budapest, Hungary

[2] Hungarian Acad Sci, Res Ctr Nat Sci, Med Chem Res Grp, 2 Magyar Tudosok Korutja, H-1117 Budapest, Hungary

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 186卷

关键词：

mGlu(2) receptor; Positive allosteric modulator; Scaffold hopping; Dihydropyrazino-benzimidazoles; Pharmacophore based optimization; SCHIZOPHRENIA; PHARMACOPHORE; PHARMACOLOGY; AGONIST;

D O I：

10.1016/j.ejmech.2019.111881

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页数：17

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