Synthesis and Biological Evaluation of Nipecotic Acid Derivatives with Terminally Double-Substituted Allenic Spacers as mGAT4 Inhibitors
A series of nipecotic acid derivatives, featuring a four- and five-carbon atom allenic spacer connecting the nitrogen of the polar nipecotic acid head with up to two aromatic residues, has been synthesized. For the synthesis of the respective nipecotic acid derivatives displaying N-substituents consisting of carbon chains with a terminal allenic function with two, mostly aryl residues a CuI-catalyzed cross-coupling of diaryldiazomethanes or N-tosylhydrazones with nipecotic acid derived terminal alkynes served as a key step. Upon characterization of these compounds regarding their inhibitory potency at mGAT1-4 and binding affinity for mGAT1, a highly potent mGAT4 inhibitor has been identified, which is defined as nipecotic acid derivative with a four-carbon atom allenic spacer terminally carrying two 4-chlorophenyl residues. The (S)-enantiomer of this compound, (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 and its human equivalent hGAT-3 with pIC50 values of 6.59 {+/-} 0.01 and 6.49 {+/-} 0.10, respectively, which are significantly higher than that of the well-known mGAT4 inhibitor (S)-SNAP-5114. In vivo evaluation of this compound revealed its significant anticonvulsant activity in several mouse models of chemically- and electrically-induced seizures. In addition to this, anxiolytic-like properties of DDPM-3960 were shown. These beneficial biological effects observed in mice were not accompanied by any serious motor deficits, making DDPM-3960 an interesting lead structure for further development.