Application of pharmacokinetic studies to a novel antidepressant, E2011

1. The original drug tested here, (5R)-3-[2-(3-cyanopropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxaz olidinone (ER-4539), exhibited strong MAO-A inhibitory activity in vitro, but its bioavailability in rat was very low. After ER-4539 was administered orally to dog, a metabolite was found in plasma. 2. The metabolite was isolated by hplc after incubation with dog liver microsomal preparations. Its structure, determined by ms and nmr analysis, was alpha-hydroxy-ER-4539. The configuration of the alpha-hydroxy metabolite was (S), determined in comparison with the authentic sample of (R) and (S) by hplc. The isolated metabolite had potent MAO-A inhibitory action in vitro, indicating that it would have antidepressant action. 3. (5R)-3-[2-((1S)-3-Cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011), the synthesized metabolite, has been improved in regard to biopharmaceutical characteristics in rat and dog.