Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives with N‐Arylalkynyl Substituents

A new scaffold of highly potent and mGAT1‐selective inhibitors has been developed. Compounds in this class are characterized by an alkyne‐type spacer connecting nipecotic acid with an aromatic moiety. Preliminary evaluations made it apparent that a nipecotic acid derivative with an N‐butynyl linker and a terminal 2‐biphenyl residue exhibiting a binding affinity (pKi) of 7.61±0.03 to mGAT1 and uptake inhibition (pIC50) of 7.00±0.06 selective for mGAT1 could serve as a hit compound. Docking calculations for compounds based on this structure in an hGAT1 homology modeling study indicated binding affinities similar to or even higher than that of the well‐known mGAT1 inhibitor tiagabine. Synthesis of the designed compounds was readily carried out by two consecutive cross‐coupling reactions, giving flexible access to variously substituted biphenyl subunits. With an appropriate substitution pattern of the biphenyl moiety, the binding affinity of enantiopure (R)‐nipecotic acid derivatives to mGAT1 increased to pKi=8.33±0.01, and the uptake inhibitory potency up to pIC50=7.72±0.02. Stable alkyne‐type spacer: A series of N‐substituted nipecotic acid derivatives with various 2‐biphenyl moieties attached via an N‐alkynyl linker were synthesized as potential GAT1 inhibitors. Some 2′,4′‐disubstituted derivatives were found to be highly potent in binding and uptake assays and display high subtype selectivity for GAT1.