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Pharmacokinetic properties of enantiomerically pure GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold
- Source :
- Journal of Pharmaceutical and Biomedical Analysis. 172:214-222
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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 logD7.4 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 logD7.4 value was recorded for the prototypical GluN2B antagonist ifenprodil (logD7.4 = 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.
- Subjects :
- Stereochemistry
Metabolite
Clinical Biochemistry
Glucuronidation
Pharmaceutical Science
Ether
Receptors, N-Methyl-D-Aspartate
01 natural sciences
Analytical Chemistry
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Glucuronides
Piperidines
Drug Discovery
medicine
Ifenprodil
Animals
Humans
Rats, Wistar
Biotransformation
Spectroscopy
Phenol
010405 organic chemistry
010401 analytical chemistry
Stereoisomerism
Benzazepines
Human serum albumin
Rats
0104 chemical sciences
Mice, Inbred C57BL
chemistry
Lipophilicity
Microsomes, Liver
Enantiomer
Glucuronide
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 07317085
- Volume :
- 172
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmaceutical and Biomedical Analysis
- Accession number :
- edsair.doi.dedup.....39d66c2b353588ece084e640fc64568f