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 (S)-enantiomer,
(S)-1-[4,4-bis(4-chlorophenyl)buta-2,3-dien-1-yl]piperidine-3-carboxylic
acid [(S)-8d, 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 (S)-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.