Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives by Suzuki-Miyaura Cross-Coupling Reactions

A new series of potent and selective mGAT1 inhibitors has been identified, featuring a nipecotic acid residue and an N‐butenyl linker with a 2‐biphenyl residue at the ω‐position. Docking, combined with MD calculations, revealed a binding mode for the new compounds similar to that of tiagabine, the only mGAT1 inhibitor currently approved as antiepileptic drug. For the synthesis, a Suzuki–Miyaura cross‐coupling reaction was used as a key step by which variously substituted biaryl subunits were assembled. Biological evaluation revealed several compounds that possess binding affinities and inhibitory potencies toward mGAT1, together with subtype selectivities against mGAT2–mGAT4 that were similar to or even higher than those for tiagabine. A derivative carrying the 2′,4′‐dichloro‐2‐biphenyl moiety attached to N‐but‐3‐enylnipecotic acid at the terminal position of the linker chain was found to be the most potent binder, with the racemic form of the compound displaying a binding affinity of 8.05±0.13 (pKi), while the R enantiomer exhibited an affinity value of 8.33±0.06 (pKi). Exploring the gap: Guided by molecular modeling studies, a series of nipecotic acid derivatives with different 2‐biphenyl moieties on an N‐butenyl linker were synthesized as potential GAT1 inhibitors. A 2′,4′‐dichlorobiphenyl‐2‐yl derivative was found to be highly potent in binding and uptake assays and to display high subtype selectivity for GAT1.