title: Synthesis, anticonvulsant activity and metabolism of 4-chlor-3-methylphenoxyethylamine derivatives of trans-2-aminocyclohexan-1-ol.
abstract: In this study, we report the synthesis, spectral characterization, antiepileptic activity and biotransformation of three new, chiral, N-aminoalkyl derivatives of trans - 2 aminocyclohexan-1-ol: (R enantiomer), (S enantiomer) and (racemate). Antiepileptic activity of the titled compounds was studied using MES and scMet. Moreover, in this study, the biotransformation of , and in microbial model (Cunninghamella), liver microsomal assay as well as in silico studies (MetaSite) was evaluated. Studies have indicated that , and have good antiepileptic activity in vivo, comparable to valproate. Biotransformation assays showed that the most probable metabolite (indicated in every tested assays) was . The microbial model as well as in silico study showed no difference in biotransformation between tested enantiomers. However, in a rat liver microsomal study compound and (R and S enantiomer) had different main metabolite - for and for . MS/MS fragmentation allowed us to predict the structures of obtained metabolites, which were in agreement with 1°alcohol () and carboxylic acid (). Our research has shown that microbial model, microsomal assay, and computational methods can be included as useful and reliable tools in early ADME-Tox assays in the process of developing new drug candidates.
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University, Medical College, Cracow, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Kubowicz
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D020093:Cunninghamella / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005021:Ethylamines / Q000737:chemistry; D008658:Inactivation, Metabolic; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: C000602171:4-chlor-3-methylphenoxyethylamine; D000927:Anticonvulsants; D005021:Ethylamines
keywords: Anticonvulsant activity; Biotransformation; Cunninghamella; Enantiomers; Liver microsomes