Pharmacokinetic properties of enantiomerically pure GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold

Abstract Recently, the eutomers of highly potent GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold were identified. Herein, pharmacokinetic properties regarding lipophilicity, plasma protein binding (PPB) and metabolism are analyzed. The log D 7.4 values of 1.68 for phenol 1 and 2.46 for methyl ether 2 are in a very good range for CNS agents. A very similar log D 7.4 value was recorded for the prototypical GluN2B antagonist ifenprodil (log D 7.4  = 1.49). The herein developed high performance affinity chromatography (HPAC) method using human serum albumin as stationary phase led to PPB of 3-benzazepines ( R )- 1 - 3 and ( S )- 1 - 3 of 76–98%. Upon incubation with mouse liver microsomes, ( R )- 1 - 3 and ( S )- 1 - 3 showed moderate to high metabolic stability. The ( R )-configured eutomers turned out to be metabolically more stable than their ( S )-configured distomers. During phase I metabolism of 3-benzazepines 1 - 3 hydroxylations at both aromatic rings, the aliphatic side chain and the seven-membered ring were observed. O -demethylation of methyl ether ( S )- 2 was faster than O -demethylation of its enantiomer ( R )- 2 . In phase I biotransformation the phenol eutomer ( R )- 1 showed comparable stability as ifenprodil. In phase II biotransformation, glucuronidation of the phenolic (only 1 ) and benzylic hydroxy groups was observed. Both enantiomers formed the same type of metabolites, respectively, but in different amounts. Whereas, the benzylic hydroxy group of ( R )- 2 was glucuronidated preferably, predominant benzylic glucuronidation of ( S )- 3 was detected. Mouse liver microsomes produced the glucuronide of phenol 1 (main metabolite) in larger amounts than rat liver microsomes.