N‐Substituted Nipecotic Acids as (S)‐SNAP‐5114 Analogues with Modified Lipophilic Domains

Potential mGAT4 inhibitors derived from the lead substance (S)‐SNAP‐5114 have been synthesized and characterized for their inhibitory potency. Variations from the parent compound included the substitution of one of its aromatic 4‐methoxy and 4‐methoxyphenyl groups, respectively, with a more polar moiety, including a carboxylic acid, alcohol, nitrile, carboxamide, sulfonamide, aldehyde or ketone function, or amino acid partial structures. Furthermore, it was investigated how the substitution of more than one of the aromatic 4‐methoxy groups affects the potency and selectivity of the resulting compounds. Among the synthesized test substances (S)‐1‐{2‐[(4‐formylphenyl)bis(4‐methoxyphenyl)‐methoxy]ethyl}piperidine‐3‐carboxylic acid, that features a carbaldehyde function in place of one of the aromatic 4‐methoxy moieties of (S)‐SNAP‐5114, was found to have a pIC(50) value of 5.89±0.07, hence constituting a slightly more potent mGAT4 inhibitor than the parent substance while showing comparable subtype selectivity.