Synthesis and Biological Evaluation of Nipecotic Acid Derivatives with Terminally Double-Substituted Allenic Spacers as mGAT4 Inhibitors

Within a series of nipecotic acid derivatives with a four- and five-carbon atom allenic spacer, respectively, connecting the nitrogen of nipecotic acid with up to two aromatic residues, a highly potent mGAT4 inhibitor has been identified. Its (<i>S</i>)-enantiomer, (<i>S</i>)-1-[4,4-bis(4-chlorophenyl)buta-2,3-dien-1-yl]piperidine-3-carboxylic acid [(<i>S</i>)-<b>8d</b>, DDPM-3960], displays potencies in the higher nanomolar range at mGAT4 (pIC₅₀ = 6.59 ± 0.01) and its human equivalent hGAT-3 (pIC₅₀ = 6.49 ± 0.10). It is thus significantly more potent than the well-known mGAT4 inhibitor (<i>S</i>)-SNAP-5114. Molecular docking rationalizes the enantioselectivity of the inhibitory potency. DDPM-3960 is highly bound to serum proteins (>99%), has good brain penetration and stability. It revealed significant anticonvulsant activity in several mouse models of chemically- and electrically induced seizures. Additionally, anxiolytic-like properties of DDPM-3960 were found. These beneficial biological effects observed in mice were accompanied by sedation but not motor impairments, making DDPM-3960 an interesting lead structure for further development.