Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach

被引：12

作者：

Ledneczki, Istvan ^{[1
]}

Tapolcsanyi, Pal ^{[1
]}

Gabor, Eszter ^{[1
]}

Visegrady, Andras ^{[1
,2
]}

Vass, Marton ^{[1
]}

Eles, Janos ^{[1
]}

Holm, Patrik ^{[5
]}

Horvath, Anita ^{[1
]}

Pocsai, Aniko ^{[1
]}

Maho, Sandor ^{[1
]}

Greiner, Istvan ^{[3
]}

Kramos, Balazs ^{[4
]}

Beni, Zoltan ^{[4
]}

Koti, Janos ^{[4
]}

Kancz, Anna E. ^{[1
]}

Than, Marta ^{[2
]}

Kolok, Sandor ^{[2
]}

Laszy, Judit ^{[2
]}

Balazs, Ottilia ^{[2
]}

Bugovits, Gyula ^{[2
]}

Nagy, Jozsef ^{[2
]}

Vastag, Monika ^{[2
]}

Szajli, Agota ^{[1
]}

Bozo, Eva ^{[1
]}

Levay, Gyorgy ^{[2
]}

Lendvai, Balazs ^{[2
]}

Nemethy, Zsolt ^{[2
]}

机构：

[1] Gedeon Richter Plc, Dept Chem, Budapest, Hungary

[2] Gedeon Richter Plc, Pharmacol & Drug Safety Res, Budapest, Hungary

[3] Gedeon Richter Plc, Res Management, Budapest, Hungary

[4] Gedeon Richter Plc, Spectroscop Res Dept, Budapest, Hungary

[5] Orion Pharma, Turku, Finland

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 214卷

关键词：

Nicotinic alpha 7 receptor; Positive allosteric modulator; Scaffold hopping; Structure activity relationship; Cognitive improvement; 4-(5-(4-CHLOROPHENYL)-2-METHYL-3-PROPIONYL-1H-PYRROL-1-YL)BENZENESULFONAMIDE A-867744; BINDING; ACTIVATION; BRAIN;

D O I：

10.1016/j.ejmech.2021.113189

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (alpha 7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of alpha 7 nACh receptors in the cognitive processes. (C) 2021 Elsevier Masson SAS. All rights reserved.

引用

页数：29

共 41 条

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