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

Falck, Evamaria; Begrow, Frank; Verspohl, Eugen J.; Wünsch, Bernhard

doi:10.1016/j.jpba.2014.01.017

Cited by 21 publications

(12 citation statements)

References 16 publications

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“…At first, the biotransformation was investigated in vitro by incubation of 9c with mouse liver microsomes, NADPH, and glucuronic acid activated with UDP (uridyldiphopsphate glucuronic acid, UDPGA). The samples were analyzed after an incubation period of 90 min by various liquid chromatography–mass spectrometry (LC–MS) methods. , …”

Section: Resultsmentioning

confidence: 99%

“…The samples were analyzed after an incubation period of 90 min by various liquid chromatography−mass spectrometry (LC−MS) methods. 39,40 This procedure led to the detection of three main metabolites of 9c. The structures of these metabolites were analyzed by their retention times, exact masses, and fragmentation patterns (MS 2 experiments).…”

Section: Metabolism Of 9cmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

et al. 2021

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Herein, relationships between the structures of 1-aminoethyl-substituted chromenes and their antimalarial activities were thoroughly investigated. At first, the methyl moiety in the side chain was removed to eliminate chirality. The hydrogenation state of the benzopyran system, the position of the phenolic OH moiety, and the distance of the basic amino moiety toward both aromatic rings were varied systematically. 1-Benzopyran-5-ol 8b (IC50 = 10 nM), 1-benzopyran-7-ol 9c (IC50 = 38 nM), and the aminoalcohol 19c (IC50 = 17 nM) displayed antiplasmodial activity with IC50 values below 50 nM. To identify the mechanism of action, inhibition of three key enzymes by 9c was investigated. 9c was not able to reduce the number of Plasmodia in erythrocytes of mice. This low in vivo activity was explained by fast clearance from blood plasma combined with rapid biotransformation of 9c. Three main metabolites of 9c were identified by liquid chromatography–mass spectrometry (LC–MS) methods.

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Section: Resultsmentioning

confidence: 99%

Section: Metabolism Of 9cmentioning

confidence: 99%

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

et al. 2021

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“…In WMS-1410 (3) the flexible β-aminoalcohol moiety of ifenprodil is integrated into a 3-benzazepine ring, [22] which resulted in increased receptor selectivity and metabolic stability. [23,24] Thus, the metabolically more stable benzoxazolone system of besonprodil (2) and the conformationally restricted 3-benzazepine system of WMS-1410 (3), leading to higher receptor selectivity, should be combined in one compound 4. In this study, we focus on the synthesis of novel oxazolo-annulated 3-benzazepines 4 designed as more selective and metabolically more stable analogs of ifenprodil.…”

Section: Introductionmentioning

confidence: 99%

“…In WMS‐1410 ( 3 ) the flexible β‐aminoalcohol moiety of ifenprodil is integrated into a 3‐benzazepine ring, [ 22 ] which resulted in increased receptor selectivity and metabolic stability. [ 23,24 ]…”

Section: Introductionmentioning

confidence: 99%

Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators

Markus

Schepmann

Wünsch

2022

Archiv der Pharmazie

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To improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil ( 2) and the 3-benzazepone moiety of WMS-1410 (3) were merged to obtain oxazolobenzazepines of type 4. The 5-(hydroxyethyl)benzoxazolone 7 representing the first key intermediate was prepared in four steps starting with the 4-(2-hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N-sulfonylated glycine esters established the necessary side chain. The intramolecular Friedel-Crafts acylation of acid 12a containing the N-tosyl protective group led upon decarbonylation exclusively to the tricyclic tetrahydroisoquinoline 14. Protection of the amino moiety by the stronger electron-withdrawing triflyl group resulted in the desired 3-benzazepine 15 without the formation of analogous isoquinoline. The triflyl protective group was cleaved off by K 2 CO 3 -induced elimination of trifluoromethanesulfinate. In a one-pot three-step procedure, various oxazolobenzazepinediones 15 were obtained, which were reduced to afford the desired secondary alcohols 18.

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“…However, the metabolically labile phenol is still present in 3. [35,36] In besonprodil (4), the benzylic secondary alcohol of ifenprodil (1) and Ro 25-6981 (2) is replaced bioisosterically by a sulfoxide, and the distance between the benzene ring and the piperidine ring is similar to the distance in Ro 25-6981 (2). The most important modification of 4 is the bioisosteric replacement of the phenol present in 1-3 by a benzoxazolone, which is no longer prone to fast glucuronidation [37] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Phenol—Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B‐selective N‐methyl‐d‐aspartate receptor antagonists

Markus

Schreiber

Goerges

et al. 2022

Archiv der Pharmazie

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Tricyclic tetrahydrooxazolo[4,5-h]-[3]benzazepin-9-ols 22 were designed as phenol bioisosteres of tetrahydro-3-benzazepine-1,7-diols. Key features of the synthesis are the introduction of the trifluoromethylsulfonyl and allyl protective groups at the heterocyclic N-atoms. Two methods were developed to convert the triflyl-protected ketone 16 into tricyclic alcohols 21 bearing various N-substituents. According to the first method, trifluoromethanesulfinate was removed by K 2 CO 3 . Following the selective reduction of the imino moiety of 17 with NaBH(OAc) 3 afforded the aminoketone 18, which was reductively alkylated and reduced. According to the second method, both the imine and the ketone of the iminoketone 17 were reduced with NaBH 4 to yield the aminoalcohol 20, which was alkylated or reductively alkylated to form tertiary amines 21f-21r. In the last step, the allyl protective group of 21 was removed with RhCl 3 and HCl to obtain oxazolones 22. In receptor binding studies using [ 3 H]ifenprodil as radioligand ketone, 22m showed the highest GluN2B affinity (K i = 88 nM). However, a reduced affinity toward GluN2B subunit-containing N-methyl-D-aspartate (NMDA) receptors was observed for oxazolones 22 compared to bioisosteric 3-benzazepine-1,7-diols. High selectivity of 22m for the ifenprodil binding site of GluN2B-NMDA receptors over the 1-(1-phenylcyclohexyl)piperidine binding site and σ 2 receptors was observed, but only negligible selectivity over σ 1 receptors. In two-electrode voltage clamp experiments, the 4-phenylbutyl derivative 22d (K i = 422 nM) demonstrated 80% inhibition of ion flux at a concentration of 1 µM. The differences in GluN2B affinity and inhibitory activity are explained by docking studies. In conclusion, 22d is regarded as a novel scaffold of highly potent GluN1/GluN2B antagonists.

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

Cited by 21 publications

References 16 publications

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators

Phenol—Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B‐selective N‐methyl‐d‐aspartate receptor antagonists

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