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Huber, Simone K.; Hoefner, Georg and Wanner, Klaus T. (2019): Application of the concept of oxime library screening by mass spectrometry (MS) binding assays to pyrrolidine-3-carboxylic acid derivatives as potential inhibitors of gamma-aminobutyric acid transporter 1 (GAT1). In: Bioorganic & Medicinal Chemistry, Vol. 27, No. 13: pp. 2753-2763

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In the present study, the concept of oxime library screening by MS Binding Assays was successfully extended to N-substituted lipophilic pyrrolidine-3-carboxylic acid derivatives in the pursuit of varying the amino acid motif in order to identify new inhibitors for GAT1 and to broaden structure-activity-relationships for this target, the most abundant GABA transporter in the central nervous system. For the screening, 28 different oxime sublibraries were employed that were generated by simple condensation reaction of an excess of pyrrolidine-3-carboxylic acid derivatives carrying a hydroxylamine functionality with various sub-libraries each assembled of eight aldehydes with broadly varying chemical structures and functionalities. The compounds responsible for the activity of an oxime sub-library were identified by deconvolution experiments performed by employing single oximes. Binding affinities of the oxime hits were confirmed in full-scale competitive MS Binding Assays. Thereby, oxime derivatives with a 1,1'-biphenyl moiety were found as the first inhibitors of mGAT1 comprising a pyrrolidine- 3-carboxylic acid motif with affinities in the submicromolar range.

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