Abstract
Aiming at the identification of new hGAT3 inhibitors, oxime libraries comprising a total of more than 1100 compounds were generated by reaction of various aldehyde and ketone libraries with hydroxylamines that comprised isoserine, 4-amino-2-hydroxybutyric acid, 4-amino-3-hydroxybutyric or nipecotic acid subunits. The formed oxime libraries were tested for their inhibitory potency at hGAT3 using an MS transporter assay. Several hits were identified displaying inhibitory potencies in the low micromolar range. All of these compounds having in common a diphenylmethylene partial structure as lipophilic domain, which is unprecedented for hGAT3 inhibitors. 1-[2-({[bis(4-chlorophenyl)methylene]amino}oxy)ethyl]piperidine-3-carboxylic acid was found to be the most potent compound of tested oxime (pIC 50 =5.17± 0.12) displaying an inhibitory potency close to the potency of the enantiopure benchmark hGAT3 inhibitor ( S )-SNAP-5114.
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