Identification of Pyrrolidine‐3‐acetic Acid Derived Oximes as Potent Inhibitors of γ‐Aminobutyric Acid Transporter 1 through Library Screening with MS Binding Assays

Abstract

In this study, pyrrolidine‐3‐acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ‐aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine‐3‐acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution experiments to identify single oximes responsible for the observed activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine‐3‐acetic acid motif were found, of which the most potent oxime, possessing a 2′,4′‐dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi=7.87±0.01).

Overview of Recent Strategic Advances in Medicinal Chemistry

“…Hydrazone 88 bearing a 2′,4′-dichlorobiphenyl moiety was identified as a robust binder with low nanomolar affinity (p K i = 8.1). Further optimization afforded 89 (p K i = 6.9) as a stable carba analogue of hydrazone …”