In vitro and in vivo biotransformation of WMS-1410, a potent GluN2B selective NMDA receptor antagonist

•Biotransformation of the GluN2B antagonist WMS-1410 is investigated.•Phase I and phase II metabolites generated in vitro and in vivo are identified.•The phenolic group represents the metabolically most labile position.•WMS-1410 is metabolically more stable than the lead compound ifenprodil.

Structural modification of the GluN2B selective NMDA receptor antagonist ifenprodil led to the 3-benzazepine WMS-1410 with similar GluN2B affinity but higher receptor selectivity. Herein the in vitro and in vivo biotransformation of WMS-1410 is reported. Incubation of WMS-1410 with rat liver microsomes and different cofactors resulted in four hydroxylated phase I metabolites, two phase II metabolites and five combined phase I/II metabolites. With exception of catechol 4, these metabolites were also identified in the urine of a rat treated with WMS-1410. However the metabolites 7, 8 and 12 clearly show that the catechol metabolite 4 was also formed in vivo. As shown for ifenprodil the phenol of WMS-1410 represents the metabolically most reactive structural element. The biotransformation of WMS-1410 is considerably slower than the biotransformation of ifenprodil indicating a higher metabolic stability. From the viewpoint of metabolic stability the bioisosteric replacement of the phenol of WMS-1410 by a metabolically more stable moiety should be favourable.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide