ANALYSIS OF DOG AND RAT PLASMA FOR METABOLITES OF A NEW ISOINDOLINE ANXIOLYTIC, DN-2327, BY LIQUID-CHROMATOGRAPHY THERMOSPRAY MASS-SPECTROMETRY AND TANDEM MASS-SPECTROMETRY

Combined liquid chromatography/thermospray mass spectrometry (full scan) and its tandem mass spectrometry (precursor ion, product ion and neutral loss scan) were used to characterize rat and dog plasma metabolites of an anxiolytic candidate (DN-2327; (+/-)-2(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)carbonylmethyl]isoindolin-1-one). The results indicated that DN-2327 was metabolized to M-I by hydrolysis of the dioxolane ring which was subsequently reduced at the carbonyl moiety to form M-II. M-II was further metabolized to diol isomers, M-III and M-IV, by hydroxylation on the hydroxypiperidine moiety. M-V was an acyclic diol resulting from cleavage of the piperidine ring followed by reduction of the aldehyde. By the methodology used here, detailed structural information could be obtained without recourse to individual metabolite isolation and this provided a great saving in time and effort.