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.
Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan.
T
T
Naitoh
T
T
Horie
S
S
Nagato
T
T
Kagaya
A
A
Kubota
K
K
Akasaka
D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D052160:Benzothiazoles; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics*; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics*; D023303:Oxazolidinones; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics*
D000928:Antidepressive Agents; D052160:Benzothiazoles; C091708:E 2011; C091709:ER 4539; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D013844:Thiazoles; D006899:Mixed Function Oxygenases