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Eur J Med Chem. 2016 Jun 30;116:136-146. doi: 10.1016/j.ejmech.2016.03.065. Epub 2016 Mar 28.

Benzimidazolone bioisosteres of potent GluN2B selective NMDA receptor antagonists.

Author information

1
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
2
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.

Abstract

Overactivation of the NMDA receptor is associated with excitotoxic events leading to neurodegenerative processes as observed during the development of Alzheimer's disease, ParFnson's disease, Chorea Huntington and epilepsy. Negative allosteric modulators addressing selectively the ifenprodil binding site of GluN2B subunit containing NMDA receptors are of major interest due to their neuroprotective potential accompanied by few side effects. Herein benzimidazolone bioisosteres of potent GluN2B antagonists 1-5 were designed and synthesized. A seven step sequence provided the central intermediate 19 in 28% yield. Elimination of water, methylation, epoxidation, epoxide rearrangement and finally reductive amination afforded the [7]annulenobenzimidazolone 30 with a 3-phenylpropylamino substituent in 6-position. Although 30 fits nicely into the pharmacophore of potent GluN2B antagonists, the gluN2B binding affinity of 30 was only moderate (Ki = 697 nM). Additionally, 30 shows low selectivity over the σ2 receptor (Ki = 549 nM). The moderate GluN2B affinity was explained by the rigid tricyclic structure of the [7]annulenobenzimidazolone 30.

KEYWORDS:

Benzimidazolone bioisosteres; GluN2B selective; NMDA antagonists; Receptor selectivity; Tricyclic benzo[7]annulenamines

PMID:
27061977
DOI:
10.1016/j.ejmech.2016.03.065
[Indexed for MEDLINE]

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