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.
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页数：17
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